DROSHA

Summary

DROSHA (drosha ribonuclease III, HGNC:17904) is a protein-coding gene on chromosome 5p13.3, encoding Ribonuclease 3 (Q9NRR4). Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis. It is a selective cancer dependency (DepMap: 35.6% of cell lines).

This gene encodes a ribonuclease (RNase) III double-stranded RNA-specific ribonuclease and subunit of the microprocessor protein complex, which catalyzes the initial processing step of microRNA (miRNA) synthesis. The encoded protein cleaves the stem loop structure from the primary microRNA (pri-miRNA) in the nucleus, yielding the precursor miRNA (pre-miRNA), which is then exported to the cytoplasm for further processing. In a human cell line lacking a functional copy of this gene, canonical miRNA synthesis is reduced. Somatic mutations in this gene have been observed in human patients with kidney cancer.

Source: NCBI Gene 29102 — RefSeq curated summary.

At a glance

• Gene–disease (curated): neurodevelopmental disorder (Moderate, GenCC)
• GWAS associations: 6
• Clinical variants (ClinVar): 262 total — 9 pathogenic
• Regional missense constraint (gnomAD): 2 of 8 regions constrained (≈7% of expected missense variation)
• GTEx eGene: eQTL in 39 tissues, sQTL in 39 (q < 0.05)
• Cancer driver (intOGen): loss-of-function (tumor-suppressor-like) across 3 cancer types (inferred from mutation patterns)
• Cancer dependency (DepMap): dependent in 35.6% of screened cell lines
• Constraint (gnomAD): pLI 1.00 (loss-of-function intolerant), LOEUF 0.39 (moderately constrained)
• MANE Select transcript: NM_001382508
• Interaction hub: 4,252 STRING partners (top 1% of genes corpus-wide)
• Notable: 262 clinical variants but no curated precision-oncology (CIViC) evidence yet

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17904
Approved symbol	DROSHA
Name	drosha ribonuclease III
Location	5p13.3
Locus type	gene with protein product
Status	Approved
Aliases	RNASE3L, Etohi2, HSA242976, RN3
Ensembl gene	ENSG00000113360
Ensembl biotype	protein_coding
OMIM	608828
Entrez	29102

Gene structure

Transcript identifiers

Ensembl transcripts: 56 — 38 protein_coding, 8 retained_intron, 6 protein_coding_CDS_not_defined, 4 nonsense_mediated_decay

MANE Select: ENST00000344624

Transcript support level (Ensembl TSL; 1 = fully mRNA-supported): TSL 1: 3, TSL 2: 4, TSL 3: 4, TSL 4: 6, TSL 5: 3

ENST00000344624, ENST00000504133, ENST00000504361, ENST00000505601, ENST00000507174, ENST00000507438, ENST00000509067, ENST00000509608, ENST00000510178, ENST00000510375, ENST00000511367, ENST00000511778, ENST00000511803, ENST00000512076, ENST00000512124, ENST00000512166, ENST00000512302, ENST00000512885, ENST00000513349, ENST00000514927, ENST00000866936, ENST00000866937, ENST00000866938, ENST00000866939, ENST00000866940, ENST00000866941, ENST00000866942, ENST00000866943, ENST00000866944, ENST00000866945, ENST00000866946, ENST00000866947, ENST00000866948, ENST00000926013, ENST00000926014, ENST00000926015, ENST00000926016, ENST00000926017, ENST00000926018, ENST00000926019, ENST00000926020, ENST00000926021, ENST00000926022, ENST00000926023, ENST00000926024, ENST00000926025, ENST00000926026, ENST00000926027, ENST00000944647, ENST00001062337, ENST00001062338, ENST00001062339, ENST00001062340, ENST00001105662, ENST00001105663, ENST00001138793

RefSeq mRNA: 3 — MANE Select: NM_001382508 NM_001100412, NM_001382508, NM_013235

CCDS: CCDS47194, CCDS47195

Canonical transcript exons

ENST00000344624 — 36 exons

Exon	Start	End
ENSE00000734381	31511035	31511176
ENSE00000804475	31514988	31515219
ENSE00000971062	31504555	31504635
ENSE00001083029	31449281	31449419
ENSE00001083052	31448547	31448607
ENSE00001083063	31437239	31437298
ENSE00001155496	31400494	31401562
ENSE00001164856	31515454	31515564
ENSE00001164865	31521123	31521215
ENSE00001165063	31493207	31493293
ENSE00001165072	31495286	31495372
ENSE00001200656	31508621	31508775
ENSE00001382130	31526079	31526912
ENSE00002059584	31530798	31530924
ENSE00002078271	31531450	31531525
ENSE00003477768	31431576	31431678
ENSE00003479095	31406853	31406945
ENSE00003483056	31472063	31472232
ENSE00003488514	31484881	31484962
ENSE00003488777	31466182	31466281
ENSE00003492847	31422787	31422944
ENSE00003495301	31435765	31435864
ENSE00003497453	31467939	31468063
ENSE00003509487	31409056	31409159
ENSE00003513104	31429475	31429545
ENSE00003513167	31421272	31421377
ENSE00003535806	31483554	31483628
ENSE00003553515	31451533	31451640
ENSE00003559530	31529040	31529105
ENSE00003559690	31405677	31405723
ENSE00003568687	31424427	31424471
ENSE00003576274	31464236	31464343
ENSE00003578158	31486491	31486562
ENSE00003628897	31410746	31410887
ENSE00003641174	31409250	31409332
ENSE00003912705	31531990	31532093

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.18.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 32.3371 / max 387.1359, expressed in 1811 samples.

Highest expression (Bgee): endothelial cell, ventricular zone, germinal epithelium of ovary, cortical plate, Brodmann (1909) area 23.

Genetic regulation across tissues (GTEx eQTL / sQTL)

DROSHA is an eGene in GTEx v10 — its expression is genetically regulated (eQTL) in 39 tissues and its splicing (sQTL) in 39 (q < 0.05). Strongest associations first; slope = normalized effect of the lead variant’s alternative allele.

showing 20 of 78 significant tissue × QTL associations:

Tissue	QTL	q-value	Slope	Lead variant
Cells Cultured fibroblasts	sqtl	3.0e-89	-1.09	5:31531512:A:G
Muscle Skeletal	sqtl	1.3e-68	-1.13	5:31531512:A:G
Artery Tibial	sqtl	1.5e-46	-0.97	5:31532682:A:G
Thyroid	sqtl	5.3e-46	-0.96	5:31531512:A:G
Cells EBV-transformed lymphocytes	sqtl	4.6e-45	-1.25	5:31531512:A:G
Thyroid	eqtl	6.5e-45	+0.54	5:31528354:C:T
Skin Sun Exposed Lower leg	sqtl	1.6e-44	-0.90	5:31531512:A:G
Nerve Tibial	eqtl	1.1e-39	+0.44	5:31528354:C:T
Nerve Tibial	sqtl	9.4e-33	-0.83	5:31531512:A:G
Adipose Subcutaneous	sqtl	7.3e-30	-0.86	5:31531512:A:G
Skin Not Sun Exposed Suprapubic	sqtl	3.9e-28	-0.83	5:31531512:A:G
Lung	sqtl	2.1e-25	-0.74	5:31531512:A:G
Adipose Visceral Omentum	sqtl	4.3e-25	-0.79	5:31531512:A:G
Adipose Visceral Omentum	eqtl	5.7e-25	+0.40	5:31528354:C:T
Artery Tibial	eqtl	2.7e-24	-0.29	5:31528520:T:C
Adipose Subcutaneous	eqtl	1.0e-23	+0.38	5:31528354:C:T
Artery Aorta	sqtl	1.3e-23	-0.92	5:31531512:A:G
Breast Mammary Tissue	eqtl	5.2e-23	+0.42	5:31528626:C:T
Breast Mammary Tissue	sqtl	1.6e-21	-0.87	5:31531512:A:G
Esophagus Muscularis	sqtl	1.8e-20	-0.81	5:31533845:T:C

FANTOM5 promoters

4 alternative TSS:

Promoter ID	TPM avg	Samples expressed
61158	30.8273	1809
61159	0.6521	357
61157	0.5012	212
61156	0.3565	172

Top tissues by expression

showing 100 of 288 tissues by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
endothelial cell	CL:0000115	98.18	gold quality
ventricular zone	UBERON:0003053	97.44	gold quality
germinal epithelium of ovary	UBERON:0001304	97.28	gold quality
cortical plate	UBERON:0005343	97.26	gold quality
Brodmann (1909) area 23	UBERON:0013554	97.02	gold quality
right hemisphere of cerebellum	UBERON:0014890	96.87	gold quality
ganglionic eminence	UBERON:0004023	96.77	gold quality
cerebellar hemisphere	UBERON:0002245	96.75	gold quality
cerebellar cortex	UBERON:0002129	96.69	gold quality
middle temporal gyrus	UBERON:0002771	96.54	gold quality
sural nerve	UBERON:0015488	96.39	gold quality
colonic epithelium	UBERON:0000397	96.19	gold quality
adenohypophysis	UBERON:0002196	96.16	gold quality
parietal pleura	UBERON:0002400	96.03	gold quality
primary visual cortex	UBERON:0002436	95.97	gold quality
cerebellum	UBERON:0002037	95.94	gold quality
visceral pleura	UBERON:0002401	95.80	gold quality
pleura	UBERON:0000977	95.40	gold quality
pituitary gland	UBERON:0000007	95.39	gold quality
tibia	UBERON:0000979	95.37	gold quality
cervix squamous epithelium	UBERON:0006922	95.37	silver quality
left ovary	UBERON:0002119	95.31	gold quality
mucosa of transverse colon	UBERON:0004991	95.27	gold quality
right ovary	UBERON:0002118	95.20	gold quality
right frontal lobe	UBERON:0002810	95.18	gold quality
secondary oocyte	CL:0000655	95.15	gold quality
right uterine tube	UBERON:0001302	95.15	gold quality
tendon of biceps brachii	UBERON:0008188	95.15	gold quality
gingival epithelium	UBERON:0001949	94.80	gold quality
caudate nucleus	UBERON:0001873	94.77	gold quality
tibial nerve	UBERON:0001323	94.74	gold quality
body of pancreas	UBERON:0001150	94.66	gold quality
nucleus accumbens	UBERON:0001882	94.50	gold quality
Brodmann (1909) area 9	UBERON:0013540	94.49	gold quality
body of uterus	UBERON:0009853	94.43	gold quality
embryo	UBERON:0000922	94.33	gold quality
ovary	UBERON:0000992	94.31	gold quality
oocyte	CL:0000023	94.29	gold quality
anterior cingulate cortex	UBERON:0009835	94.27	gold quality
putamen	UBERON:0001874	94.26	gold quality
cingulate cortex	UBERON:0003027	94.18	gold quality
epithelium of nasopharynx	UBERON:0001951	93.90	gold quality
endocervix	UBERON:0000458	93.85	gold quality
dorsolateral prefrontal cortex	UBERON:0009834	93.81	gold quality
left lobe of thyroid gland	UBERON:0001120	93.76	gold quality
right lobe of thyroid gland	UBERON:0001119	93.59	gold quality
muscle layer of sigmoid colon	UBERON:0035805	93.53	gold quality
skin of abdomen	UBERON:0001416	93.47	gold quality
amygdala	UBERON:0001876	93.46	gold quality
palpebral conjunctiva	UBERON:0001812	93.43	gold quality
C1 segment of cervical spinal cord	UBERON:0006469	93.39	gold quality
thyroid gland	UBERON:0002046	93.36	gold quality
squamous epithelium	UBERON:0006914	93.31	gold quality
ectocervix	UBERON:0012249	93.29	gold quality
esophagus squamous epithelium	UBERON:0006920	93.20	gold quality
esophagogastric junction muscularis propria	UBERON:0035841	93.16	gold quality
tendon	UBERON:0000043	93.15	gold quality
calcaneal tendon	UBERON:0003701	93.14	gold quality
choroid plexus epithelium	UBERON:0003911	93.13	gold quality
skin of leg	UBERON:0001511	93.04	gold quality
endometrium	UBERON:0001295	93.00	gold quality
lower esophagus mucosa	UBERON:0035834	92.98	gold quality
parotid gland	UBERON:0001831	92.97	gold quality
metanephros cortex	UBERON:0010533	92.92	gold quality
amniotic fluid	UBERON:0000173	92.91	gold quality
small intestine Peyer’s patch	UBERON:0003454	92.91	gold quality
lower esophagus muscularis layer	UBERON:0035833	92.91	gold quality
transverse colon	UBERON:0001157	92.90	gold quality
lower esophagus	UBERON:0013473	92.90	gold quality
brain	UBERON:0000955	92.88	gold quality
forebrain	UBERON:0001890	92.78	gold quality
neocortex	UBERON:0001950	92.77	gold quality
vagina	UBERON:0000996	92.76	gold quality
minor salivary gland	UBERON:0001830	92.76	gold quality
telencephalon	UBERON:0001893	92.69	gold quality
ascending aorta	UBERON:0001496	92.67	gold quality
apex of heart	UBERON:0002098	92.65	gold quality
thoracic aorta	UBERON:0001515	92.58	gold quality
uterus	UBERON:0000995	92.57	gold quality
popliteal artery	UBERON:0002250	92.57	gold quality
tibial artery	UBERON:0007610	92.57	gold quality
omental fat pad	UBERON:0010414	92.56	gold quality
left coronary artery	UBERON:0001626	92.55	gold quality
peritoneum	UBERON:0002358	92.55	gold quality
aorta	UBERON:0000947	92.52	gold quality
tonsil	UBERON:0002372	92.52	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	92.52	gold quality
adipose tissue of abdominal region	UBERON:0007808	92.45	gold quality
cerebral cortex	UBERON:0000956	92.42	gold quality
pancreas	UBERON:0001264	92.36	gold quality
esophagus	UBERON:0001043	92.35	gold quality
occipital lobe	UBERON:0002021	92.33	gold quality
spleen	UBERON:0002106	92.31	gold quality
prostate gland	UBERON:0002367	92.28	gold quality
female reproductive system	UBERON:0000474	92.23	gold quality
mouth mucosa	UBERON:0003729	92.20	gold quality
gingiva	UBERON:0001828	92.19	gold quality
prefrontal cortex	UBERON:0000451	92.13	gold quality
frontal cortex	UBERON:0001870	92.09	gold quality
spinal cord	UBERON:0002240	92.09	gold quality

Single-cell (SCXA)

Detected in 1 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	5.68

HPA expression

RNA tissue specificity: Low tissue specificity

showing 60 of 76 HPA tissues / cells by nTPM:

Tissue / cell	Axis	nTPM
Postcentral gyrus	tissue	48.5
Choroid plexus	tissue	47.0
Nucleus accumbens	tissue	42.0
Locus coeruleus	tissue	36.8
Caudate putamen	tissue	36.1
Hippocampus	tissue	36.0
Frontal cortex	tissue	35.4
Cerebellum	tissue	25.7
Retina	tissue	25.2
Olfactory bulb	tissue	25.1
Cerebral cortex	tissue	23.3
Putamen	tissue	23.3
Occipital cortex	tissue	23.3
Thymus	tissue	22.8
Somatosensory cortex	tissue	22.5
Temporal cortex	tissue	22.3
Basal ganglia	tissue	21.9
Hippocampal formation	tissue	21.8
Entorhinal cortex	tissue	21.8
Prefrontal cortex	tissue	21.5
Midbrain	tissue	21.5
Thalamus	tissue	21.5
Motor cortex	tissue	21.4
Skeletal muscle	tissue	20.8
Ventral forebrain	tissue	20.8
Retrosplenial and cingulate cortex	tissue	20.8
Hypothalamus	tissue	20.6
Retrosplenial cortex	tissue	20.6
Septum	tissue	20.4
Insular cortex	tissue	20.4
Periaqueductal gray	tissue	20.1
Superior colliculi	tissue	19.9
Pons	tissue	19.6
Amygdala	tissue	19.5
Epididymis	tissue	19.3
Substantia nigra	tissue	18.7
Corpus callosum	tissue	18.6
Tongue	tissue	18.3
Medulla oblongata	tissue	18.3
Spinal cord	tissue	17.8
Ovary	tissue	17.7
Tonsil	tissue	16.1
Appendix	tissue	15.0
Lymph node	tissue	14.9
Endometrium 1	tissue	14.9
Rectum	tissue	14.7
Thyroid gland	tissue	14.5
Parathyroid gland	tissue	14.3
Fallopian tube	tissue	13.7
Pancreas	tissue	13.6
Placenta	tissue	13.0
Smooth muscle	tissue	12.9
Colon	tissue	12.9
Skin 1	tissue	12.8
Duodenum	tissue	12.8
Prostate	tissue	12.8
Cervix	tissue	12.5
Stomach 1	tissue	12.4
Seminal vesicle	tissue	12.4
Pituitary gland	tissue	12.1

Brain sub-regions (HPA Brain Atlas): detected in 189; highest nTPM — Orbitofrontal gyrus, anterior (67.9), Vermis (57.0), Flocculonodular lobe (56.3), Paraventricular nucleus (54.5), Cerebellar cortex (50.6).

Regulation

Is transcription factor: yes

Downstream targets (CollecTRI)

1 targets:

Target	Regulation
CCNB1	Activation

Upstream regulators (CollecTRI, top): E2F1, E2F4

miRNA regulators (miRDB)

Targeting DROSHA by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific).

showing 30 of 49 miRNAs:

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-6758-5P	100.00	66.21	1470
HSA-MIR-4795-3P	100.00	74.62	4024
HSA-MIR-6856-5P	100.00	65.47	1298
HSA-MIR-6833-3P	100.00	70.63	3197
HSA-MIR-4768-5P	100.00	69.49	2861
HSA-MIR-4668-3P	100.00	68.74	2635
HSA-MIR-8485	100.00	77.57	4731
HSA-MIR-196A-1-3P	99.99	72.15	2772
HSA-MIR-548C-3P	99.99	74.01	7587
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-548P	99.98	72.25	3784
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-MIR-6845-3P	99.94	66.88	1439
HSA-MIR-6780A-5P	99.88	66.69	2776
HSA-MIR-4698	99.84	71.41	4303
HSA-MIR-3121-3P	99.82	71.96	3630
HSA-MIR-4713-5P	99.78	67.80	1794
HSA-MIR-1273H-5P	99.77	66.32	2471
HSA-MIR-6505-5P	99.73	69.25	1595
HSA-MIR-30B-3P	99.70	65.76	2325
HSA-MIR-3689A-3P	99.70	65.73	2306
HSA-MIR-3689B-3P	99.70	65.71	2311
HSA-MIR-3689C	99.70	65.71	2311
HSA-MIR-6779-5P	99.70	65.76	2363
HSA-MIR-10394-5P	99.65	66.83	1852
HSA-MIR-1205	99.65	66.76	1826
HSA-MIR-103A-1-5P	99.39	67.78	1545
HSA-MIR-103A-2-5P	99.39	67.72	1577
HSA-MIR-1276	99.36	68.18	1642

Functional genomics

gnomAD constraint: pLI 1, LOEUF 0.39, missense Z 4.55 — population loss-of-function intolerance (pLI ≥ 0.9 = LoF-intolerant; lower LOEUF = more constrained). gnomAD

Regional missense constraint (gnomAD)

ENST00000344624 splits into 8 regions with different missense tolerance; 2 are missense-constrained (≈7% of the expected missense variation). Missense variants in a constrained region (low observed/expected) are more likely to be pathogenic. gnomAD

Region (GRCh38)	Missense obs / exp	o/e	Constrained
5:31,401,435–31,401,514	32 / 29.2	1.09	no
5:31,401,515–31,409,261	48 / 124.9	0.38	no
5:31,409,262–31,410,833	47 / 70.6	0.67	no
5:31,410,834–31,422,855	23 / 90.6	0.25	yes (p 1.2e-12)
5:31,422,856–31,431,610	71 / 95.2	0.75	no
5:31,431,611–31,431,660	1 / 23.2	0.04	yes (p 4.0e-06)
5:31,431,661–31,515,046	460 / 774.2	0.59	no
5:31,515,047–31,529,059	536 / 535.4	1.00	no
DepMap (CRISPR cell-line fitness): dependent in 35.6% of screened cell lines.

Most-dependent cell lines (DepMap gene-effect, lower = stronger; ≤ −0.5 shown): Raji (-1.256), OCUM-1 (-1.11), G-292, clone A141B1 (-1.06), A3/KAW (-1.038), RERF-GC-1B (-1.036), SK-NEP-1 (-1.034), HCC-366 (-1.033), KARPAS-422 (-1.03), HUP-T3 (-1.012), WM793 (-1.01), G-401 (-1.001), HCC2998 (-0.993), TTC-549 (-0.991), DK-MG (-0.985), Mac-2A (-0.98).

Literature-anchored findings (GeneRIF, showing 40)

• identification of another RNase III, human Drosha, as the core nuclease that executes the initiation step of miRNA processing in the nucleus (PMID:14508493)
• human Drosha is a component of two multi-protein complexes; both components of the smaller complex, termed Microprocessor, are necessary and sufficient in mediating the genesis of miRNAs from the primary miRNA transcript (PMID:15531877)
• Data show that human Drosha selectively cleaves RNA hairpins bearing a large (>/=10 nucleotides) terminal loop. (PMID:15565168)
• nuclear RNase III Drosha cleaves primary miRNAs (pri-miRNAs) to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic RNase III Dicer to generate mature miRNAs (PMID:15574589)
• processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences (PMID:15932881)
• Dicer gene expression in human breast cells is regulated by alternative promoter selection to alter the length and composition of the 5’-leader sequence of its mRNA (PMID:15987463)
• We found that RNASEN expression levels were enhanced in a fraction of esophageal cancers. (PMID:17121874)
• Drosha may cleave intronic miRNAs between the splicing commitment step and the excision step, thereby ensuring both miRNA biogenesis and protein synthesis from a single primary transcript. (PMID:17255951)
• identify specific miRNAs up-regulated in leukemias triggered by All1 fusions. All1 fusion protein-mediated recruitment of Drosha to target genes encoding miRNAs is demonstrated (PMID:17581865)
• miR-BHRF1-2 in 3’ cleavage of BHRF1 mRNA in the cytoplasm and Drosha in cleavage of latency III EBNA and EBV replication-associated BHRF1 transcripts in the nucleus. (PMID:17626073)
• Integrative genomics analysis of chromosome 5p gain in cervical cancer reveals target over-expressed genes, including Drosha. (PMID:18559093)
• Our findings indicate that levels of Dicer and Drosha mRNA in ovarian-cancer cells have associations with outcomes in patients with ovarian cancer. (PMID:19092150)
• The Drosha-DGCR8 complex cleaves the hairpin in the DGCR8 mRNA and thus destabilizes the mRNA; DGCR8 stabilizes Drosha protein via protein interaction; this crossregulation between Drosha and DGCR8 may contribute to the control of miRNA biogenesis. (PMID:19135890)
• The mRNA for microprocessor component DROSHA was found to be significantly upregulated in the dorsolateral prefrontal cortex in tissues from schizophrenic patients. (PMID:19721432)
• a Microprocessor, containing the RNA binding protein Dgcr8 and RNase III enzyme Drosha, is responsible for processing primary microRNAs to precursor microRNAs (PMID:19759829)
• Report dysregulation of microRNA processing enzymes Drosha and Dicer in epithelial skin tumors when compared to healthy control samples. (PMID:20210522)
• Smad proteins bind a conserved RNA sequence to promote microRNA maturation by Drosha. (PMID:20705240)
• Findings of growth promotion by Drosher silencing implies its potential use as therapeutic targets for neuroblastoma. (PMID:20805302)
• This study revealed for the first time that expression alterations of Dicer and Drosha are present in endometrial cancer tissue and could be potentially responsible for altered microRNAs profiles observed in this malignancy. (PMID:21559780)
• the selectivity of Drosha action contributes greatly to the specificity and efficiency of miRNA biogenesis (PMID:21683814)
• Drosha, an endoribonuclease best known for its role in the biogenesis of microRNAs, can also function to directly regulate viral gene expression of Kaposi’s sarcoma-associated herpesvirus (PMID:21690333)
• The authors report that Drosha cleavage of latency III BHRF1 RNA and cis-acting splicing effects inhibit splicing and inhibit BHRF1 RNA and protein expression. (PMID:21697496)
• Our results suggest that Drosha, Dicer, and Ago2 are possibly implicated in colorectal carcinoma pathobiology (PMID:21769619)
• Drosha regulates human mesenchymal stem cells cell cycle progression through a miRNA independent mechanism, potentially by regulating rRNA processing. (PMID:21794839)
• Low drosha expression is associated with breast cancer. (PMID:21898071)
• Drosha and Dicer expression was dysregulation in nasopharyngeal carcinoma compared with healthy control samples. (PMID:21953080)
• PTEN-mediated miR-21 regulation is achieved by inhibiting the interaction between the Drosha complex and RNH1, revealing previously unidentified role of PTEN in the oncogenic miR-21 biogenesis (PMID:22162762)
• mesenchymal stromal cells from MDS patients show low gene and protein expression of DICER1 and DROSHA which are involved in the microRNA biogenesis, as well as their target gene SBDS. (PMID:22371183)
• The results showed that genetic variants of DROSHA may modify the risk of abnormal semen parameters, which could result in male infertility. (PMID:22381205)
• DGCR8 and Drosha are targeted post-transcriptionally to chromosome 19 microRNA cluster pri-miRNAs as a preformed complex but dissociate separately. (PMID:22393237)
• results provide novel evidence that Drosha, is probably involved in the pathobiology of human smooth muscle neoplasms (PMID:22394132)
• Data show that down-regulation of either Dicer or Drosha had no effect on the sensitivity of cells to irradiation. (PMID:22479364)
• Rare Drosha splice variants are deficient in microRNA processing but do not affect general microRNA expression in cancer cells (PMID:22496623)
• Gene silencing of hepatitis B virus X protein by RNA interference significantly restored the expression of Drosha. (PMID:22554933)
• Drosha, Dicer, Argonaute 1, and Argonaute 2 are differentially expressed at different metastatic sites in ovarian carcinoma compared with primary carcinomas. (PMID:22647351)
• Dicer, Drosha, and Exportin 5 genes were up-regulated in bladder urothelial carcinoma compared to normal urothelium. Silencing these genes induced cell proliferation inhibition and apoptosis in bladder urothelial carcinoma cells. (PMID:22766726)
• DGCR8-mediated cleavage of snoRNAs was independent of Drosha, suggesting the involvement of DGCR8 in cellular complexes with other endonucleases. Binding of DGCR8 to cassette exons is a new mechanism for regulation of alternatively spliced isoforms. (PMID:22796965)
• A subset of Lin28 mRNA targets are destabilized in a Drosha-dependent manner. (PMID:22935707)
• Drosha protein potentially plays an important role in breast cancer progression. (PMID:23225145)
• Data indicate that tumour sample showed a significantly higher Drosha expression versus normal mucosa, while Dicer levels did not differ. (PMID:23266047)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	drosha	ENSDARG00000055563
mus_musculus	Drosha	ENSMUSG00000022191
rattus_norvegicus	Drosha	ENSRNOG00000013451
drosophila_melanogaster	drosha	FBGN0026722
caenorhabditis_elegans	drsh-1	WBGENE00009163

Mouse-model phenotypes

Observed phenotypes of the mouse ortholog (MGI:1261425) from MGI (Alliance of Genome Resources) — knockout/mutant phenotypes, ranked by annotation count. 62 distinct phenotype terms.

Mouse phenotype (MP)	Records
decreased body size	2
increased leukocyte cell number	1
increased granulocyte number	1
abnormal coat/ hair morphology	1
abnormal hair follicle morphology	1
small hair follicles	1
waved hair	1
alopecia	1
absent kidney	1
abnormal kidney development	1
enlarged spleen	1
enlarged lymph nodes	1
decreased thymocyte number	1
scaly skin	1
epidermal hyperplasia	1
decreased locomotor activity	1
cyanosis	1
abnormal immune system physiology	1
abnormal T cell activation	1
increased activated T cell number	1
intestinal inflammation	1
liver inflammation	1
lung inflammation	1
blood vessel inflammation	1
respiratory distress	1

+37 more (showing top 25).

Additional cross-species homologs

Sequence homologs in species beyond Ensembl Compara’s model organisms, by Diamond local protein alignment (% sequence identity; best hit per species). Lower-identity rows are more distant homologs. The matched accessions’ gene symbols aren’t in biobtree yet, so each row shows the UniProt accession.

Organism	UniProt	Identity	Method
Cricetulus griseus	A0MQH0	96.8%	Diamond
Xenopus laevis	A0A974H8H3	95.3%	Diamond
Xenopus tropicalis	B3DLA6	95.3%	Diamond
Gallus gallus	Q25BN1	91.8%	Diamond
Caenorhabditis briggsae	Q61XX9	63.7%	Diamond
Neurospora crassa OR74A	Q7SCC1	57.1%	Diamond
Saccharomyces cerevisiae S288C	Q02555	39.2%	Diamond

Genomic neighbors (locus context)

Genes flanking this one on the chromosome (NCBI/Entrez gene neighborhood). Positional context only — some neighbors share regulatory elements (bidirectional promoters, antisense/overlapping transcripts), but chromosomal adjacency is not itself a functional relationship (see Interactions for that).

Symbol	Type	Entrez
C5orf22	protein-coding	55322
CDH6	protein-coding	1004
PDZD2	protein-coding	23037

Protein

Protein identifiers

Ribonuclease 3 — Q9NRR4 (reviewed: Q9NRR4)

Alternative names: Protein Drosha, Ribonuclease III, p241

All UniProt accessions (4): Q9NRR4, E5RHD1, H0YB67, H7C5U6

UniProt curated annotations — full annotation on UniProt →

Function. Ribonuclease III double-stranded (ds) RNA-specific endoribonuclease that is involved in the initial step of microRNA (miRNA) biogenesis. Component of the microprocessor complex that is required to process primary miRNA transcripts (pri-miRNAs) to release precursor miRNA (pre-miRNA) in the nucleus. Within the microprocessor complex, DROSHA cleaves the 3’ and 5’ strands of a stem-loop in pri-miRNAs (processing center 11 bp from the dsRNA-ssRNA junction) to release hairpin-shaped pre-miRNAs that are subsequently cut by the cytoplasmic DICER to generate mature miRNAs. Involved also in pre-rRNA processing. Cleaves double-strand RNA and does not cleave single-strand RNA. Involved in the formation of GW bodies. Plays a role in growth homeostasis in response to autophagy in motor neurons.

Subunit / interactions. Component of the microprocessor complex, or pri-miRNA processing protein complex, which is composed of DROSHA and DGCR8. The microprocessor complex is a heterotrimer; each of the two DROSHA RNase III domains binds one DGCR8 (via C-terminal region). Interacts with SP1 and SNIP1. Interacts with SRRT/ARS2. Interacts with CPSF3 and ISY1; this interaction is in an RNA dependent manner. Interacts with PUS10; interaction promotes pri-miRNAs processing.

Subcellular location. Nucleus. Nucleolus. Cytoplasm.

Tissue specificity. Ubiquitous.

Post-translational modifications. Degraded by autophagy in response to neuronal activity in motor neurons.

Cofactor. Each RNase III domain binds at least one Mg(2+) or Mn(2+) ion.

Domain organisation. The 2 RNase III domains form an intramolecular dimer where the domain 1 cuts the 3’strand while the domain 2 cleaves the 5’strand of pri-miRNAs, independently of each other.

Similarity. Belongs to the ribonuclease III family.

Isoforms (4)

UniProt ID	Names	Canonical?
Q9NRR4-1	1	yes
Q9NRR4-2	2
Q9NRR4-3	3
Q9NRR4-4	4

RefSeq proteins (3): NP_001093882, NP_001369437, NP_037367 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000999	RNase_III_dom	Domain
IPR011907	RNase_III	Family
IPR014720	dsRBD_dom	Domain
IPR036389	RNase_III_sf	Homologous_superfamily
IPR044442	RNAse_III_DSRM__animal	Domain
IPR058938	Helical_CED_Drosha	Domain

Pfam: PF00035, PF00636, PF14622, PF26050

Enzyme classification (BRENDA)

• EC 3.1.26.3 — ribonuclease III (BRENDA: 65 organisms, 299 substrates, 50 inhibitors, 32 Km, 23 kcat entries)

Substrate kinetics (BRENDA)

6 substrates with measured Km, best-characterized 6. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
R1.1 RNA	—	15
RNA	0.0003–0.34	4
515 BP DSRNA	—	3
AA-[16S[MICRO-HP]RNA]	0.001	1
MN2+	38	1
POLY(IC)	0.4	1

UniProt features (154 total): helix 57, strand 28, mutagenesis site 17, binding site 14, compositionally biased region 8, turn 7, splice variant 5, sequence conflict 5, region of interest 4, domain 3, modified residue 2, sequence variant 2, chain 1, site 1

Structure

Experimental structures (PDB)

12 structures by resolution:

PDB	Title	Method	Resolution (Å)
9ASM	Human Drosha and DGCR8 in complex with Pri-let-7f1	ELECTRON MICROSCOPY	2.8
9ASO	Human Drosha and DGCR8 in complex with Pri-let-7a2	ELECTRON MICROSCOPY	2.9
9ASQ	Human Drosha, DGCR8 and SRSF3 in complex with Pri-let-7f1	ELECTRON MICROSCOPY	3
5B16	X-ray structure of DROSHA in complex with the C-terminal tail of DGCR8.	X-RAY DIFFRACTION	3.2
9ASN	Human Drosha and DGCR8 in complex with Pri-miR-98	ELECTRON MICROSCOPY	3.2
9ASP	Human Drosha and DGCR8 in complex with Pri-let-7a1	ELECTRON MICROSCOPY	3.2
6V5B	Human Drosha and DGCR8 in complex with Primary MicroRNA (MP/RNA complex) - Active state	ELECTRON MICROSCOPY	3.7
6LXD	Pri-miRNA bound DROSHA-DGCR8 complex	ELECTRON MICROSCOPY	3.9
6LXE	DROSHA-DGCR8 complex	ELECTRON MICROSCOPY	4.2
6V5C	Human Drosha and DGCR8 in complex with Primary MicroRNA (MP/RNA complex) - partially …	ELECTRON MICROSCOPY	4.4
2KHX	Drosha double-stranded RNA binding motif	SOLUTION NMR
2NA2	DROSHA QUAD MUTANT DOUBLE-STRANDED RNA BINDING COMPETENT	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NRR4-F1	70.94	0.40

Human Protein Atlas

Protein class: Enzymes, ENZYME proteins, Hydrolases, Predicted intracellular proteins, Cancer-related genes, Essential proteins

Protein evidence: Evidence at protein level

Subcellular location (HPA, imaging): nucleoplasm; cytosol

Antibody reliability (HPA): IF supported

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1)

Position	Role
1215	important for activity

Ligand- & substrate-binding residues (14)

Position	Role
536	Zn(2+)
538	Zn(2+)
549	Zn(2+)
561	Zn(2+)
609	Zn(2+)
676	Zn(2+)
680	Zn(2+)
969	Mg(2+)
1026	Zn(2+)
1042	Mg(2+)
1045	Mg(2+)
1147	Mg(2+)
1219	Mg(2+)
1222	Mg(2+)

Post-translational modifications (2)

Type	Positions
Phosphoserine	355, 373

Mutagenesis-validated functional residues (17)

Position	Phenotype
536	impairs protein folding and stability; when associated with a-538.
538	impairs protein folding and stability; when associated with a-536.
561	impairs protein folding and stability.
622–623	abolishes rnase activity.
676	impairs protein folding and stability.
835–836	abolishes rnase activity.
914	impairs rnase activity.
923	abolishes rnase activity; when associated with a-927.
927	abolishes rnase activity; when associated with a-923.
938–940	abolishes rnase activity.
993	no effect on pri-mirna processing activity.
1045	impairs pri-mirna processing activity. abolishes cleavage of the 3’ strand. abolishes enzyme activity; when associated with q-1222.
1077	loss of one dgcr8 interaction site; no effect on the second dgcr8 interaction site.
1171	no effect on pri-mirna processing activity.
1194	abolishes interaction with dgcr8.
1222	impairs pri-mirna processing activity. abolishes cleavage of the 5’ strand. abolishes enzyme activity; when associated with q-1045.
1243	abolishes interaction with dgcr8.

Function

Pathways and Gene Ontology

Reactome pathways

1 curated (TAS) of 3; 0 disease pathways. Curated-first; evidence = TAS (manually curated) vs IEA (electronic inference).

3 pathways:

ID	Pathway	Evidence
R-HSA-203927	MicroRNA (miRNA) biogenesis	curated
R-HSA-211000	Gene Silencing by RNA	—
R-HSA-74160	Gene expression (Transcription)	—

MSigDB gene sets: 154 (showing top): GOBP_REGULATION_OF_CELL_ACTIVATION, GOBP_RIBOSOME_BIOGENESIS, GOMF_ENDONUCLEASE_ACTIVITY, GOMF_RNA_NUCLEASE_ACTIVITY, GOBP_INFLAMMATORY_RESPONSE, GOMF_NUCLEASE_ACTIVITY, HUMMERICH_BENIGN_SKIN_TUMOR_UP, MITSIADES_RESPONSE_TO_APLIDIN_DN, GOBP_REGULATION_OF_LEUKOCYTE_DIFFERENTIATION, GOBP_REGULATION_OF_HEMOPOIESIS, GOMF_RNA_ENDONUCLEASE_ACTIVITY, GOBP_REGULATION_OF_RESPONSE_TO_STRESS, GOBP_REGULATION_OF_LYMPHOCYTE_DIFFERENTIATION, GOBP_DEFENSE_RESPONSE_TO_GRAM_NEGATIVE_BACTERIUM, GOBP_DEFENSE_RESPONSE_TO_GRAM_POSITIVE_BACTERIUM

GO Biological Process (10): rRNA processing (GO:0006364), positive regulation of gene expression (GO:0010628), primary miRNA processing (GO:0031053), pre-miRNA processing (GO:0031054), defense response to Gram-negative bacterium (GO:0050829), defense response to Gram-positive bacterium (GO:0050830), RNA processing (GO:0006396), regulatory ncRNA-mediated gene silencing (GO:0031047), miRNA processing (GO:0035196), ribosome biogenesis (GO:0042254)

GO Molecular Function (14): lipopolysaccharide binding (GO:0001530), RNA binding (GO:0003723), ribonuclease III activity (GO:0004525), DEAD/H-box RNA helicase binding (GO:0017151), protein homodimerization activity (GO:0042803), SMAD binding (GO:0046332), metal ion binding (GO:0046872), R-SMAD binding (GO:0070412), primary miRNA binding (GO:0070878), nuclease activity (GO:0004518), endonuclease activity (GO:0004519), RNA endonuclease activity (GO:0004521), protein binding (GO:0005515), hydrolase activity (GO:0016787)

GO Cellular Component (8): nucleus (GO:0005634), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), postsynaptic density (GO:0014069), microprocessor complex (GO:0070877), glutamatergic synapse (GO:0098978), organelle (GO:0043226)

Reactome top-level categories

2 top-level categories:

Category	Pathways
Gene Silencing by RNA	1
Gene expression (Transcription)	1

GO top-level categories

41 GO namespaces:

Category	Terms
cellular anatomical structure	3
gene expression	2
miRNA processing	2
defense response to bacterium	2
nuclear lumen	2
RNA processing	1
rRNA metabolic process	1
ribosome biogenesis	1
regulation of gene expression	1
positive regulation of macromolecule biosynthetic process	1
RNA biosynthetic process	1
primary metabolic process	1
negative regulation of gene expression	1
regulatory ncRNA processing	1
ribonucleoprotein complex biogenesis	1
lipid binding	1
carbohydrate derivative binding	1
nucleic acid binding	1
RNA endonuclease activity producing 5’-phosphomonoesters, hydrolytic mechanism	1
double-stranded RNA-specific ribonuclease activity	1
enzyme binding	1
identical protein binding	1
protein dimerization activity	1
protein binding	1
cation binding	1
SMAD binding	1
RNA binding	1
catalytic activity, acting on a nucleic acid	1
nuclease activity	1
endonuclease activity	1
RNA nuclease activity	1
binding	1
catalytic activity	1
intracellular membrane-bounded organelle	1
intracellular membraneless organelle	1
intracellular anatomical structure	1
asymmetric synapse	1
postsynaptic specialization	1
nuclear protein-containing complex	1
ribonuclease III complex	1
synapse	1

Experimentally-supported GO annotations

GO terms backed by direct experimental evidence (ECO experimental codes) — 13 of 32 annotations. The rest are phylogenetic / computational / electronic (IEA).

13 experimentally-supported GO terms:

GO term	NS	Evidence
defense response to Gram-negative bacterium	BP	direct assay
defense response to Gram-positive bacterium	BP	direct assay
primary miRNA processing	BP	direct assay
microprocessor complex	CC	direct assay
nucleoplasm	CC	direct assay
DEAD/H-box RNA helicase binding	MF	physical interaction
R-SMAD binding	MF	physical interaction
RNA binding	MF	physical interaction
SMAD binding	MF	physical interaction
lipopolysaccharide binding	MF	direct assay
primary miRNA binding	MF	physical interaction
protein homodimerization activity	MF	direct assay
ribonuclease III activity	MF	direct assay

Protein interactions and networks

STRING

showing 15 of 4,252 interactions by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
DROSHA	DGCR8	Q8WYQ5	961
DROSHA	AGO2	Q9UKV8	940
DROSHA	XPO5	Q9HAV4	923
DROSHA	AGO1	Q9UL18	894
DROSHA	TARBP2	Q15633	884
DROSHA	DDX5	P17844	879
DROSHA	RNH1	P13489	846
DROSHA	PIWIL4	Q7Z3Z4	835
DROSHA	PIWIL1	Q96J94	830
DROSHA	PDCD4	Q53EL6	826
DROSHA	DICER1	Q9UPY3	782
DROSHA	DDX17	Q92841	746
DROSHA	SMAD5	Q99717	731
DROSHA	AGO4	Q9HCK5	701
DROSHA	SMAD4	Q13485	692

IntAct

Human interaction partners of DROSHA in IntAct, one row per partner (best MIscore; records = supporting IntAct interaction records).

16 partners by confidence:

Partner	Interaction type	MIscore	Records
DGCR8	physical association	0.940	8
DDX5	association	0.740	3
TP53	association	0.680	4
SMAD1	physical association	0.560	1
SRPK1	association	0.530	1
FUS	physical association	0.520	2
DYRK1A	association	0.480	2
GRB2	physical association	0.400	1
KHSRP	physical association	0.400	1
NCK1	physical association	0.400	1
SNIP1	physical association	0.400	1
SP1	physical association	0.400	1
NLRP12	physical association	0.370	1
ZNF512B	physical association	0.370	1
EPAS1	association	0.350	1
TULP3	physical association	0.000	1

BioGRID (214 interactions; top human partners by supporting records): DGCR8 (Affinity Capture-MS; 11 records), SRPK1 (Affinity Capture-MS; 6 records), CHRNA9 (Affinity Capture-MS; 3 records), DDX5 (Affinity Capture-Western; 3 records), APEX1 (Co-localization; 2 records), DYRK1A (Affinity Capture-Western; 2 records), HNRNPA1 (Proximity Label-MS; 2 records), HNRNPAB (Proximity Label-MS; 2 records), ILF3 (Affinity Capture-MS; 2 records), KHDRBS1 (Proximity Label-MS; 2 records), KHSRP (Affinity Capture-Western; 2 records), MEN1 (Affinity Capture-MS; 2 records), NR2E1 (Affinity Capture-Western; 2 records), NUDT21 (Proximity Label-MS; 2 records), RBM14 (Proximity Label-MS; 2 records)

SIGNOR signaling

showing 3 of 4 signaling interactions:

A	Effect	B	Mechanism
p38	“down-regulates activity”	DROSHA	phosphorylation
DROSHA	“form complex”	“Microprocessor complex”	binding
GSK3B	“up-regulates activity”	DROSHA	phosphorylation

Protein complexes (CORUM) (2)

Experimentally-characterized complexes this protein is a subunit of (★ = the complex contains a known drug target).

2 complexes by size:

Complex	Subunits	Members
Large Drosha complex	20	DDX1, FUS, RALY, TARDBP, DDX17, DHX15, HNRNPH1, HNRNPM, DDX3X, DROSHA, HNRNPU, HNRNPUL1, ILF2, TAF15, DDX5, DGCR8, EWSR1, HNRNPDL, ILF3, SRPK1
Microprocessor complex	2	DGCR8, DROSHA

Disease & clinical

Cancer significance

From intOGen — cancer-driver classification: loss-of-function (tumor-suppressor-like) across 3 cancer types — LUSC, PAAD, WT.

intOGen’s role is a computational inference from cohort mutation patterns and may diverge from the gene’s curated/literature role; read it alongside the evidence above.

Genetic variants

Variant evidence for DROSHA: 262 ClinVar records (9 pathogenic / likely pathogenic); 1 PharmGKB clinical annotation; 6 GWAS associations. Per-variant detail is on Sugi Variant.

ClinVar

262 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	9
Likely pathogenic	0
Uncertain significance	138
Likely benign	50
Benign	15

Top pathogenic / likely-pathogenic (9)

Showing all 9 pathogenic / likely-pathogenic ClinVar records, ranked by ClinVar review status (expert panel → multiple submitters → single submitter), then by number of submitting labs.

Variant ID	HGVS	Classification	Review	Submitters
981828	NM_001382508.1(DROSHA):c.1498G>T (p.Glu500Ter)	Pathogenic	criteria provided, single submitter	1
4073702	NM_001382508.1(DROSHA):c.927dup (p.Glu310fs)	Pathogenic	criteria provided, single submitter	1
3393488	NM_001382508.1(DROSHA):c.3261+1G>C	Pathogenic	no assertion criteria provided	3
3393487	NM_001382508.1(DROSHA):c.403_409delinsCCACTT (p.Ala135fs)	Pathogenic	no assertion criteria provided	2
3393490	NM_001382508.1(DROSHA):c.2436_2439del (p.Asp814fs)	Pathogenic	no assertion criteria provided	2
3393485	NM_001382508.1(DROSHA):c.811C>T (p.Arg271Ter)	Pathogenic	no assertion criteria provided	1
3393486	NM_001382508.1(DROSHA):c.2883-1G>A	Pathogenic	no assertion criteria provided	1
3393489	NM_001382508.1(DROSHA):c.3548del (p.Asn1183fs)	Pathogenic	no assertion criteria provided	1
3393491	NM_001382508.1(DROSHA):c.2988A>C (p.Leu996Phe)	Pathogenic	no assertion criteria provided	1

Per-variant reference — Sugi Variant

Explore DROSHA’s pathogenic and likely-pathogenic variants individually — each with its ClinVar classification and conditions, applied ACMG criteria (ClinGen expert panel, where curated), the calibrated in-silico predictors (AlphaMissense, REVEL, SaProt, conservation), gnomAD frequency, and the predictor-disagreement QC signal — on Sugi Variant.

SpliceAI

Top 10 splice-impact sites by Δscore (adjacent positions with the same effect merged into one range; 26 predictions of 3,716):

Position(s)	Effect	Δscore	Sites
5:31422832	donor_gain	1.0000
5:31422945–31422946	acceptor_loss	1.0000	5
5:31422949	acceptor_gain	1.0000
5:31435736	donor_gain	1.0000
5:31436201	donor_gain	1.0000
5:31437237–31437238	donor_loss	1.0000	5
5:31437299–31437300	acceptor_loss	1.0000	4
5:31451531–31451532	donor_loss	1.0000	4
5:31451642	acceptor_loss	1.0000	3
5:31464211	donor_gain	1.0000

AlphaMissense

5,316 missense substitutions predicted likely pathogenic (of 9,127 scored), across 988 residues. Top 20 hotspot residues, ranked by the number of likely-pathogenic substitutions (of those reachable by a single-nucleotide change), then by mean score:

Residue	Likely-pathogenic substitutions	Mean am_pathogenicity	Max am_pathogenicity
M949	9	0.999	1.000
M1322	9	0.995	0.999
M1040	9	0.979	1.000
M834	9	0.961	0.999
M1022	9	0.961	1.000
M740	9	0.959	0.995
M1337	9	0.951	0.999
M1154	9	0.944	1.000
M530	9	0.939	0.996
M1241	9	0.935	0.999
M908	9	0.927	0.998
M1146	9	0.926	1.000
M862	9	0.895	0.999
M1196	9	0.895	1.000
H549	8	1.000	1.000
D755	8	1.000	1.000
D758	8	1.000	1.000
D855	8	1.000	1.000
D911	8	1.000	1.000
D973	8	1.000	1.000

HPA cancer prognostics

RNA cancer specificity: Low cancer specificity

Human Protein Atlas survival analysis — favorable = higher expression predicts better survival.

3 prognostic cancer types:

Cancer	Prognostic	p-value
Kidney Renal Clear Cell Carcinoma (TCGA)	favorable	0.000228
Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA)	unfavorable	0.000404
Kidney Chromophobe (TCGA)	unfavorable	0.00049

Disease associations

OMIM: gene MIM:608828 | disease phenotypes:

GenCC curated gene-disease

1 curated gene-disease records:

Disease	Classification	Inheritance	Records
neurodevelopmental disorder	Moderate	Autosomal dominant

Genomics England panels (PanelApp)

Clinical diagnostic gene panels including this gene (8 panels, 3 green/diagnostic-grade). Confidence: green = diagnostic, amber = moderate.

8 panels:

Panel	Rating
Early onset or syndromic epilepsy	green
Severe microcephaly	green
Unexplained death in infancy and sudden unexplained death in childhood	green
Hypotonic infant	amber
Intellectual disability	amber
Leukodystrophy, childhood onset	amber
Paediatric disorders	amber
Skeletal dysplasia	amber

Mondo (4): pineoblastoma (MONDO:0016722), hepatoblastoma (MONDO:0018666), hereditary breast ovarian cancer syndrome (MONDO:0003582), neurodevelopmental disorder (MONDO:0700092)

Orphanet (3): Pineoblastoma (Orphanet:251909), Hepatoblastoma (Orphanet:449), Hereditary breast and/or ovarian cancer syndrome (Orphanet:145)

GWAS associations

6 associations:

Study	Trait	p-value
GCST90013466_4	Height	2e-9
GCST90013466_59	Height	3e-8
GCST006991_2	Cerebrospinal fluid t-tau levels in Alzheimer’s disease dementia	9e-7
GCST007231_1	Tuberculosis	2e-6
GCST008480_6	Lung function (FEV1)	3e-6
GCST90013468_2	Height	3e-6

EFO canonical traits (from GWAS)

2 canonical traits:

EFO ID	Trait name
EFO:0004760	t-tau measurement
EFO:0004314	forced expiratory volume

MeSH disease descriptors

3 disease descriptors:

Descriptor	Name	Tree numbers
D018197	Hepatoblastoma	C04.557.435.380
D061325	Hereditary Breast and Ovarian Cancer Syndrome	C04.588.180.483; C04.588.322.455.431; C04.700.517; C12.050.351.500.056.630.705.431; C12.050.351.937.418.685.431; C12.100.250.056.630.705.431; C12.900.418.685.431; C16.320.700.517; C17.800.090.500.483; C19.344.410.431; C19.391.630.705.431
D065886	Neurodevelopmental Disorders	F03.625

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (CPIC guideline: no)

PharmGKB clinical annotations

1 annotations by evidence level (1 strongest → 4):

Variant	Association	Level	Drugs	Phenotypes
rs639174	Toxicity	3	cyclophosphamide;cytarabine;daunorubicin;mercaptopurine;methotrexate;prednisone;vincristine	Acute lymphoblastic leukemia

PharmGKB variants

1 variants:

Variant	Genes	Level	Score	#Clin annots	Drugs
rs639174	DROSHA	3	2.50	1	cyclophosphamide;cytarabine;daunorubicin;mercaptopurine;methotrexate;prednisone;vincristine

PharmGKB variant annotations

Per-publication pharmacogenomic findings for this gene (significant associations).

1 published findings:

Variant	Drug(s)	Category	Finding	PMID
rs639174	cyclophosphamide, cytarabine, daunorubicin, mercaptopurine, methotrexate, prednisone, vincristine	Toxicity	Allele T is associated with increased risk of Drug Toxicity when treated with cyclophosphamide, cytarabine, daunorubicin, mercaptopurine, methotrexate, prednisone and vincristine in children with Precursor Cell Lymphoblastic Leukemia-Lymphoma as compared to allele C.	PMID:24614921

CTD chemical–gene interactions

43 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	decreases expression	2
sodium arsenite	decreases expression, increases abundance	2
potassium chromate(VI)	decreases expression, increases expression, affects cotreatment	2
methacrylaldehyde	increases abundance, affects cotreatment, increases oxidation	2
Acrolein	affects cotreatment, increases oxidation, increases abundance	2
Arsenic	increases abundance, affects methylation, decreases expression	2
Ozone	affects cotreatment, increases oxidation, increases abundance	2
Valproic Acid	affects expression, decreases expression	2
FR900359	increases phosphorylation	1
TAK-243	increases sumoylation	1
dicrotophos	increases expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	increases oxidation, increases abundance, affects cotreatment	1
beta-lapachone	decreases expression, increases expression	1
arsenite	affects binding, decreases reaction	1
mono-(2-ethylhexyl)phthalate	affects cotreatment, increases expression	1
zinc chloride	affects cotreatment, affects expression	1
butyraldehyde	decreases expression	1
monobutyl phthalate	affects cotreatment, increases expression	1
coumarin	increases phosphorylation	1
beta-methylcholine	affects expression	1
epigallocatechin gallate	affects cotreatment, decreases expression	1
chromium hexavalent ion	affects expression	1
mono-benzyl phthalate	affects cotreatment, increases expression	1
monoisononylphthalate	affects cotreatment, increases expression	1
ICG 001	decreases expression	1
abrine	decreases expression	1
mono-isobutyl phthalate	affects cotreatment, increases expression	1
monoethyl phthalate	affects cotreatment, increases expression	1
Resveratrol	affects cotreatment, increases expression	1

Cellosaurus cell lines

4 cell lines: 3 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2W3	Abcam HEK293T DROSHA KO	Transformed cell line	Female
CVCL_B8EW	Abcam HCT 116 DROSHA KO	Cancer cell line	Male
CVCL_B8UZ	Abcam MCF-7 DROSHA KO	Cancer cell line	Female
CVCL_B9H4	Abcam A-549 DROSHA KO	Cancer cell line	Male

Clinical trials (associated diseases)

Via MONDO — disease-level, not drug-specific.

showing 60 of 396 trials:

NCT	Phase	Status	Title
NCT04586348	Phase 4	UNKNOWN	Prenatal Iodine Supplementation and Early Childhood Neurodevelopment
NCT04873115	Phase 4	UNKNOWN	Double-blind, Placebo-controlled, Randomized Clinical Trial Comparing the Efficacy and Safety of Sialanar Plus orAl rehabiLitation Against Placebo Plus Oral Rehabilitation for chIldren and Adolescents With seVere Sialorrhoea and Neurodisabilties,
NCT02933333	Phase 4	UNKNOWN	G-CSF Alone or Combination With GM-CSF on Prevention and Treatment of Infection in Children With Malignant Tumor
NCT00556283	Phase 4	COMPLETED	RCT: STARR vs Biofeedback
NCT02562170	Phase 4	COMPLETED	Protexa® Versus TiLoopBra® in Immediate Breast Reconstruction- A Pilot Study
NCT02559102	Phase 3	COMPLETED	Dexmedetomidine Sedation Versus General Anaesthesia for Inguinal Hernia Surgery in Infants
NCT02757079	Phase 3	COMPLETED	Study of the Efficacy and Safety of NPC-15 for Sleep Disorders of Children With Neurodevelopmental Disorders
NCT06915480	Phase 3	RECRUITING	Reducing Missed Appointments
NCT07377032	Phase 3	RECRUITING	TAP-GRIN: Interventional Study on Patients With GRIN-related Neurodevelopmental Disorders
NCT03017326	Phase 3	ACTIVE_NOT_RECRUITING	Paediatric Hepatic International Tumour Trial
NCT03533582	Phase 3	ACTIVE_NOT_RECRUITING	Cisplatin and Combination Chemotherapy in Treating Children and Young Adults With Hepatoblastoma or Liver Cancer After Surgery
NCT04478292	Phase 3	RECRUITING	A Multi-institutional Study for Treatment of Children With Newly Diagnosed Hepatoblastoma Using a Modified PHITT Strategy
NCT00226044	Phase 3	COMPLETED	Rectal and Oral Omeprazole Treatment of Reflux Disease in Infants.
NCT00673335	Phase 3	COMPLETED	Letrozole in Preventing Breast Cancer in Postmenopausal Women With a BRCA1 or BRCA2 Mutation
NCT00685256	Phase 3	COMPLETED	Standard Genetic Counseling With or Without a Decision Guide in Improving Communication Between Mothers Undergoing BRCA1/2 Testing and Their Minor-Age Children
NCT03162276	Phase 3	UNKNOWN	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT02909959	Phase 2	COMPLETED	Sulforaphane for the Treatment of Young Men With Autism Spectrum Disorder
NCT06081348	Phase 2	RECRUITING	Sertraline vs. Placebo in the Treatment of Anxiety in Children and AdoLescents With NeurodevelopMental Disorders
NCT06352372	Phase 2	COMPLETED	Safety and Efficacy of tPBM for Epileptiform Activity in Autism
NCT01154816	Phase 2	COMPLETED	Alisertib in Treating Young Patients With Recurrent or Refractory Solid Tumors or Leukemia
NCT02011126	Phase 2	WITHDRAWN	Imetelstat Sodium in Treating Younger Patients With Relapsed or Refractory Solid Tumors
NCT02867592	Phase 2	ACTIVE_NOT_RECRUITING	Cabozantinib-S-Malate in Treating Younger Patients With Recurrent, Refractory, or Newly Diagnosed Sarcomas, Wilms Tumor, or Other Rare Tumors
NCT03155620	Phase 2	ACTIVE_NOT_RECRUITING	Targeted Therapy Directed by Genetic Testing in Treating Pediatric Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphomas, or Histiocytic Disorders (The Pediatric MATCH Screening Trial)
NCT03210714	Phase 2	ACTIVE_NOT_RECRUITING	Erdafitinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With FGFR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213652	Phase 2	ACTIVE_NOT_RECRUITING	Ensartinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With ALK or ROS1 Genomic Alterations (A Pediatric MATCH Treatment Trial)
NCT03213665	Phase 2	COMPLETED	Tazemetostat in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With EZH2, SMARCB1, or SMARCA4 Gene Mutations (A Pediatric MATCH Treatment Trial)
NCT03213678	Phase 2	COMPLETED	Samotolisib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With TSC or PI3K/MTOR Mutations (A Pediatric MATCH Treatment Trial)
NCT03213704	Phase 2	ACTIVE_NOT_RECRUITING	Larotrectinib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With NTRK Fusions (A Pediatric MATCH Treatment Trial)
NCT03220035	Phase 2	COMPLETED	Vemurafenib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With BRAF V600 Mutations (A Pediatric MATCH Treatment Trial)
NCT03233204	Phase 2	COMPLETED	Olaparib in Treating Patients With Relapsed or Refractory Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Defects in DNA Damage Repair Genes (A Pediatric MATCH Treatment Trial)
NCT03526250	Phase 2	COMPLETED	Palbociclib in Treating Patients With Relapsed or Refractory Rb Positive Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With Activating Alterations in Cell Cycle Genes (A Pediatric MATCH Treatment Trial)
NCT03698994	Phase 2	ACTIVE_NOT_RECRUITING	Ulixertinib in Treating Patients With Advanced Solid Tumors, Non-Hodgkin Lymphoma, or Histiocytic Disorders With MAPK Pathway Mutations (A Pediatric MATCH Treatment Trial)
NCT04195555	Phase 2	ACTIVE_NOT_RECRUITING	Ivosidenib in Treating Patients With Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With IDH1 Mutations (A Pediatric MATCH Treatment Trial)
NCT04284774	Phase 2	ACTIVE_NOT_RECRUITING	Tipifarnib for the Treatment of Advanced Solid Tumors, Lymphoma, or Histiocytic Disorders With HRAS Gene Alterations, a Pediatric MATCH Treatment Trial
NCT04320888	Phase 2	ACTIVE_NOT_RECRUITING	Selpercatinib for the Treatment of Advanced Solid Tumors, Lymphomas, or Histiocytic Disorders With Activating RET Gene Alterations, a Pediatric MATCH Treatment Trial
NCT05302921	Phase 2	COMPLETED	Neoadjuvant Dual Checkpoint Inhibition and Cryoablation in Relapsed/Refractory Pediatric Solid Tumors
NCT06638931	Phase 2	RECRUITING	Agnostic Therapy in Rare Solid Tumors
NCT07300449	Phase 2	RECRUITING	A Prospective Multicenter Clinical Study of SCCG Protocol and ctDNA 5hmc in Predicting the Chemotherapy Sensitivity and Monitoring the Recurrence and Metastasis of Hepatoblastoma in Children and Adolescents
NCT00179803	Phase 2	COMPLETED	Stem Cell Transplant for High Risk Central Nervous System (CNS) Tumors
NCT01217437	Phase 2	COMPLETED	Temozolomide and Irinotecan Hydrochloride With or Without Bevacizumab in Treating Young Patients With Recurrent or Refractory Medulloblastoma or CNS Primitive Neuroectodermal Tumors
NCT02596828	Phase 2	COMPLETED	Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma
NCT03127345	Phase 2	WITHDRAWN	Omega 3 Fatty Acid Treatment for Pediatric Musculoskeletal Health
NCT00253539	Phase 2	COMPLETED	Arzoxifene or Tamoxifen in Preventing Breast Cancer in Premenopausal Women at High Risk for Breast Cancer
NCT00305695	Phase 2	COMPLETED	Zoledronate or Observation in Maintaining Bone Mineral Density in Patients Who Are Undergoing Surgery to Remove Both Ovaries
NCT00321633	Phase 2	COMPLETED	Carboplatin or Docetaxel in Treating Women With Metastatic Genetic Breast Cancer
NCT01333748	Phase 2	COMPLETED	Search Allelic Imbalance of Expression of BRCA Genes in Hereditary Risk of Breast and/or Ovarian Cancer
NCT01367639	Phase 2	COMPLETED	Trial of Inquiry Based Stress Reduction (IBSR) Program for BRCA1/2 Mutation Carriers
NCT00503191	Phase 1	COMPLETED	NeuroModulation Technique Treatment of Autism
NCT04475848	Phase 1	COMPLETED	A Study to Investigate the Safety, Tolerability, Pharmacokinetics, Pharmacodynamics and Food Effect of RO6953958 in Healthy Participants
NCT06300398	Phase 1	COMPLETED	IAMA-6 Oral Dose Study in Healthy Adults
NCT01331135	Phase 1	COMPLETED	Aflac ST0901 CHOANOME - Sirolimus in Solid Tumors
NCT02390843	Phase 1	COMPLETED	Simvastatin With Topotecan and Cyclophosphamide in Relapsed and/or Refractory Pediatric Solid and CNS Tumors
NCT03618381	Phase 1	ACTIVE_NOT_RECRUITING	EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04093648	Phase 1	WITHDRAWN	T Cells co- Expressing a Second Generation Glypican 3-specific Chimeric Antigen Receptor With Cytokines Interleukin-21 and 15 as Immunotherapy for Patients With Liver Cancer (TEGAR)
NCT04308330	Phase 1	RECRUITING	Vorinostat in Combination With Chemotherapy in Relapsed/Refractory Solid Tumors and CNS Malignancies
NCT04337177	Phase 1	ACTIVE_NOT_RECRUITING	Flavored, Oral Irinotecan VAL-413 (Orotecan®) Given With Temozolomide for Treatment of Recurrent Pediatric Solid Tumors
NCT04483778	Phase 1	ACTIVE_NOT_RECRUITING	B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults
NCT04897321	Phase 1	RECRUITING	B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients With Solid Tumors (3CAR)
NCT06198296	Phase 1	RECRUITING	Immunotherapy For Adults With GPC3-Positive Solid Tumors Using IL-15 and IL-21 Armored GPC3-CAR T Cells
NCT07148050	Phase 1	RECRUITING	Immunotherapy for Solid Tumor Malignancies in Pediatrics Using Interleukin-15 and -21 Armored Glypican-3-specific Chimeric Antigen Receptor T Cells