RETREG1

Summary

RETREG1 (reticulophagy regulator 1, HGNC:25964) is a protein-coding gene on chromosome 5p15.1, encoding Reticulophagy regulator 1 (Q9H6L5). Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes.

The protein encoded by this gene is a cis-Golgi transmembrane protein that may be necessary for the long-term survival of nociceptive and autonomic ganglion neurons. Mutations in this gene are a cause of hereditary sensory and autonomic neuropathy type IIB (HSAN IIB), and this gene may also play a role in susceptibility to vascular dementia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene.

Source: NCBI Gene 54463 — RefSeq curated summary.

At a glance

• Gene–disease (curated): hereditary sensory and autonomic neuropathy (Definitive, ClinGen) — +2 more curated relationships
• GWAS associations: 5
• Clinical variants (ClinVar): 428 total — 15 pathogenic, 5 likely-pathogenic
• Phenotypes (HPO): 53
• Dosage sensitivity (ClinGen): haploinsufficiency autosomal recessive, triplosensitivity no evidence
• MANE Select transcript: NM_001034850

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:25964
Approved symbol	RETREG1
Name	reticulophagy regulator 1
Location	5p15.1
Locus type	gene with protein product
Status	Approved
Aliases	FLJ20152, JK1
Ensembl gene	ENSG00000154153
Ensembl biotype	protein_coding
OMIM	613114
Entrez	54463

Gene structure

Transcript identifiers

Ensembl transcripts: 24 — 11 protein_coding, 7 retained_intron, 3 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay

ENST00000306320, ENST00000399793, ENST00000506441, ENST00000509048, ENST00000509977, ENST00000510362, ENST00000682033, ENST00000682142, ENST00000682229, ENST00000682564, ENST00000682628, ENST00000682808, ENST00000682828, ENST00000682982, ENST00000683045, ENST00000683130, ENST00000683169, ENST00000683414, ENST00000683527, ENST00000683539, ENST00000683973, ENST00000684456, ENST00000684521, ENST00000684695

RefSeq mRNA: 2 — MANE Select: NM_001034850 NM_001034850, NM_019000

CCDS: CCDS43304, CCDS43305

Canonical transcript exons

ENST00000306320 — 9 exons

Exon	Start	End
ENSE00001430782	16565763	16565793
ENSE00001433417	16571996	16572102
ENSE00002055885	16616652	16616997
ENSE00002086008	16473053	16475234
ENSE00003506696	16481009	16481093
ENSE00003559616	16483346	16483472
ENSE00003588872	16478034	16478098
ENSE00003606051	16477662	16477788
ENSE00003621435	16478850	16478987

Expression profiles

Bgee: expression breadth ubiquitous, 283 present calls, max score 98.96.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 9.8543 / max 263.7421, expressed in 1134 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
61007	5.6298	923
61010	1.6281	644
61001	0.6963	134
61006	0.4475	181
61002	0.3053	117
61004	0.2814	140
61008	0.2712	149
61005	0.2160	110
61009	0.1974	101
60999	0.0807	36

Top tissues by expression

296 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	98.96	gold quality
diaphragm	UBERON:0001103	98.63	gold quality
heart right ventricle	UBERON:0002080	98.11	gold quality
left ventricle myocardium	UBERON:0006566	98.07	gold quality
endothelial cell	CL:0000115	97.98	silver quality
myocardium	UBERON:0002349	97.88	gold quality
deltoid	UBERON:0001476	97.81	gold quality
skeletal muscle tissue	UBERON:0001134	97.59	gold quality
gluteal muscle	UBERON:0002000	97.56	gold quality
biceps brachii	UBERON:0001507	97.49	gold quality
cardiac muscle of right atrium	UBERON:0003379	97.46	gold quality
tendon of biceps brachii	UBERON:0008188	97.44	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	97.42	gold quality
body of tongue	UBERON:0011876	97.41	gold quality
synovial joint	UBERON:0002217	97.29	gold quality
corpus callosum	UBERON:0002336	97.15	gold quality
pons	UBERON:0000988	96.81	gold quality
triceps brachii	UBERON:0001509	96.76	gold quality
calcaneal tendon	UBERON:0003701	96.59	gold quality
lateral nuclear group of thalamus	UBERON:0002736	96.57	gold quality
gastrocnemius	UBERON:0001388	96.46	gold quality
substantia nigra pars compacta	UBERON:0001965	96.45	gold quality
muscle organ	UBERON:0001630	96.43	gold quality
skeletal muscle organ	UBERON:0014892	96.43	gold quality
tendon	UBERON:0000043	96.40	gold quality
muscle of leg	UBERON:0001383	96.37	gold quality
vastus lateralis	UBERON:0001379	96.14	gold quality
trigeminal ganglion	UBERON:0001675	96.13	gold quality
nephron tubule	UBERON:0001231	96.09	gold quality
muscle tissue	UBERON:0002385	96.08	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 4.

Experiment	Marker?	Max mean expression
E-GEOD-86618	yes	264.32
E-CURD-119	yes	26.04
E-HCAD-10	yes	16.58
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

186 targeting RETREG1, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-5011-5P	100.00	83.46	5820
HSA-MIR-190A-3P	100.00	80.35	5520
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-1277-5P	100.00	73.95	5056
HSA-MIR-3163	100.00	77.23	8605
HSA-MIR-3646	100.00	73.56	5283
HSA-MIR-513B-5P	99.99	69.96	2150
HSA-MIR-3662	99.99	73.82	5684
HSA-MIR-186-5P	99.99	70.83	3707
HSA-MIR-34A-5P	99.99	71.21	1784
HSA-MIR-449A	99.99	71.05	1776
HSA-MIR-4282	99.99	75.36	6408
HSA-MIR-12136	99.98	72.81	5713
HSA-MIR-4775	99.98	75.00	6394
HSA-MIR-3688-3P	99.97	72.02	2834
HSA-MIR-34C-5P	99.97	70.45	1577
HSA-MIR-449B-5P	99.97	70.26	1580
HSA-MIR-8075	99.97	67.20	962
HSA-MIR-9-3P	99.96	70.88	2068
HSA-MIR-551B-5P	99.96	71.28	3493
HSA-MIR-548AT-5P	99.96	70.83	2666
HSA-MIR-590-3P	99.96	74.34	6478
HSA-MIR-559	99.95	72.28	3609
HSA-MIR-548AB	99.95	71.31	3488
HSA-MIR-128-3P	99.95	71.17	2484
HSA-MIR-216A-3P	99.95	71.19	2505
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-651-3P	99.94	73.48	5177
HSA-MIR-548A-5P	99.94	71.27	3482
HSA-MIR-548AD-5P	99.94	71.23	3502

Functional genomics

ClinGen dosage: haploinsufficiency 30 (autosomal recessive), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 38)

• The overexpression of JK-1(FAM134b) and its transforming capacity in normal cells may play a critical role in the molecular pathogenesis of esophageal squamous cell carcinoma. (PMID:17487424)
• show that loss-of-function mutations in FAM134B, encoding a newly identified cis-Golgi protein, cause hereditary sensory and autonomic neuropathy type II. (PMID:19838196)
• case report of homozygous nonsense mutation p.Q145X causing severe hereditary sensory neuropathy (PMID:21115472)
• The FAM134B and TNFRSF19 showed a dramatically strong synergistic epistasis in explaining the genetic dissection of the susceptibility to complex vascular dementia. (PMID:21127458)
• Homozygous FAM134B mutation was found in Turkish siblings with hereditary sensory neuropathy type 2. (PMID:24327336)
• The changes in JK1 DNA copy number associated with progression of colorectal neoplasms.A decrease in JK-1 copy number was correlated with a shorter disease-free survival time. (PMID:24825067)
• FAM134B represses cell migration in colon cancer.FAM134B has functional role in the pathogenesis of colon cancer. (PMID:24927874)
• Results show the interplay between promoter SNPs of CD39 and FAM134B results in an intercellular epistasis which influences the risk of a complex inflammatory disease. (PMID:24970562)
• Low FAM134B expression is associated with colorectal cancer. (PMID:24973512)
• selective endoplasmic reticulum (ER)-phagy via FAM134 proteins is indispensable for mammalian cell homeostasis and controls ER morphology and turnover in mice and humans (PMID:26040720)
• FAM134B protein was noted in both cytoplasm and nuclei of colon cancer cells. In cancer cells derived from stage IV colon cancer, FAM134B expression was remarkably reduced when compared to non-cancer colon cells and cancer cells derived from stage II colon cancer. FAM134B knockdown significantly (P < 0.05) increased the proliferation of colon cancer cells following lentiviral transfection. (PMID:27120410)
• These findings imply that mutation might be the major driving source of FAM134B genetic modulation in oesophageal squamous cell carcinoma. (PMID:27373372)
• NS3-mediated cleavage of FAM134B blocks the formation of endoplasmic reticulum and viral protein-enriched autophagosomes. (PMID:28102736)
• FAM134B mutation is common in colorectal cancer. The association of the mutation of this gene with adverse clinical and pathological parameters is congruent with the tumour suppressive properties of the gene (PMID:28144752)
• miR-186-5p expression promotes colorectal cancer pathogenesis by regulating tumour suppressor FAM134B (PMID:28549913)
• FAM134B promoter methylation plays a key role in regulating FAM134B expression in vitro and in vivo, which in turn contributes to the prediction of the biological aggressiveness of colorectal adenocarcinomas. (PMID:29318692)
• the expression level of JK-1 is correlated with the clinicopathological features of esophageal carcinoma (PMID:29937447)
• This study has first time reported the gene signaling networks with which FAM134B interacts and noted that FAM134B is involved in the regulation of WNT/beta-catenin pathway by EB1-mediated modulating of APC in colon cancer cells. (PMID:29964340)
• Fam134b is an oncogene that plays a crucial role in hepatocellular carcinoma via the Akt signaling pathway. (PMID:30556279)
• Results provide evidence that FAM134B is required for autophagy of procollagen. (PMID:30559329)
• FAM134B could play crucial roles in the initiation and progression of esophageal squamous cell carcinoma, and FAM134B protein expression has potential predictive value. (PMID:30794892)
• Through molecular dynamic simulations of FAM134B in flat and curved membranes, we relate the dynamic RHD structure with its two wedge-shaped transmembrane helical hairpins and two amphipathic helices to FAM134B functions in membrane-curvature induction and curvature-mediated protein sorting. (PMID:31147549)
• Overexpression of FAM134B alone in HeLa cells is sufficient to impair ER homeostasis and cause ER stress and cell death. (PMID:31748416)
• FAM134B oligomerization drives endoplasmic reticulum membrane scission for ER-phagy. (PMID:31930741)
• Novel exomic rare variants associated with venous thrombosis. (PMID:32232851)
• RETREG1/FAM134B mediated autophagosomal degradation of AMFR/GP78 and OPA1 -a dual organellar turnover mechanism. (PMID:32559118)
• MiT/TFE factors control ER-phagy via transcriptional regulation of FAM134B. (PMID:32716134)
• Overexpression of family with sequence similarity 134, member B (FAM134B) in colon cancers and its tumor suppressive properties in vitro. (PMID:32857678)
• Differential expression of full-length and NH2 terminally truncated FAM134B isoforms in normal physiology and cancer. (PMID:33052704)
• Genomics Links Inflammation With Neurocognitive Impairment in Children Living With Human Immunodeficiency Virus Type-1. (PMID:33373444)
• FAM134B-Mediated ER-phagy Upregulation Attenuates AGEs-Induced Apoptosis and Senescence in Human Nucleus Pulposus Cells. (PMID:34394825)
• Targeting FAM134B-mediated reticulophagy activates sorafenib-induced ferroptosis in hepatocellular carcinoma. (PMID:34929448)
• A regulatory circuit comprising the CBP and SIRT7 regulates FAM134B-mediated ER-phagy. (PMID:37043189)
• Molecular characterization of wild-type and HSAN2B-linked FAM134B. (PMID:37273064)
• Phenotypic features of RETREG1-related hereditary sensory autonomic neuropathy. (PMID:37448294)
• Elevated FAM134B expression induces radiation-sensitive in hepatocellular carcinoma. (PMID:37460952)
• Upregulation of FAM134B inhibits endoplasmic reticulum stress-related degradation protein expression and promotes hepatocellular carcinogenesis. (PMID:37728036)
• Excessive ER-phagy mediated by FAM134B contributes to trophoblast cell mitochondrial dysfunction in preeclampsia. (PMID:38774969)

Cross-species orthologs

1 orthologs

Organism	Symbol	Gene ID
mus_musculus	Retreg1	ENSMUSG00000022270

Protein

Protein identifiers

Reticulophagy regulator 1 — Q9H6L5 (reviewed: Q9H6L5)

Alternative names: Reticulophagy receptor 1

All UniProt accessions (10): Q9H6L5, A0A804HHX5, A0A804HIV2, A0A804HIW5, A0A804HJ37, A0A804HJI9, A0A804HJZ6, A0A804HKT1, A0A804HKW5, H0Y9U4

UniProt curated annotations — full annotation on UniProt →

Function. Endoplasmic reticulum (ER)-anchored autophagy regulator which mediates ER delivery into lysosomes through sequestration into autophagosomes. Promotes membrane remodeling and ER scission via its membrane bending capacity and targets the fragments into autophagosomes via interaction with ATG8 family proteins. Active under basal conditions. Required for collagen quality control in a LIR motif-dependent manner. Required for long-term survival of nociceptive and autonomic ganglion neurons. (Microbial infection) During SARS-CoV-2 infection, RETREG1-mediated reticulophagy is promoted by SARS-CoV-2 ORF3A protein. This induces endoplasmic reticulum stress and inflammatory responses and facilitates viral infection.

Subunit / interactions. Homooligomer; oligomerization is enhanced following endoplasmic reticulum stress and is mediated by the reticulon homology domain. Interacts with ATG8 family modifier proteins MAP1LC3A, MAP1LC3B, MAP1LC3C, GABARAP, GABARAPL1 and GABARAPL2. Shows higher affinity for GABARAPL1 than for MAP1LC3A or MAP1LC3B.

Subcellular location. Golgi apparatus. cis-Golgi network membrane. Endoplasmic reticulum membrane Endoplasmic reticulum membrane.

Tissue specificity. Overexpressed in esophageal squamous cell carcinoma.

Post-translational modifications. Phosphorylation at Ser-151 by CAMK2B enhances oligomerization and membrane scission and reticulophagy activity.

Disease relevance. Neuropathy, hereditary sensory and autonomic, 2B (HSAN2B) [MIM:613115] A form of hereditary sensory and autonomic neuropathy, a genetically and clinically heterogeneous group of disorders characterized by degeneration of dorsal root and autonomic ganglion cells, and by sensory and/or autonomic abnormalities. HSAN2B is an autosomal recessive disorder characterized by impairment of pain, temperature and touch sensation. Onset occurs in the first or second decade, with impaired nociception and progressive mutilating ulceration of the hands and feet with osteomyelitis and acroosteolysis. Amputations of the hands and feet are common. Autonomic dysfunction includes hyperhidrosis, urinary incontinence, and slow pupillary light response. The disease is caused by variants affecting the gene represented in this entry.

Domain organisation. The LIR motif interacts with ATG8 family proteins and is necessary to target the ER fragments to autophagosomes for subsequent lysosomal degradation. The reticulon homology domain provides capacity to bend the membrane and promotes ER scission. It is required for homooligomerization. This domain does not show relevant similarities with reticulon domains, preventing any domain predictions within the protein sequence.

Similarity. Belongs to the RETREG family.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9H6L5-1	1	yes
Q9H6L5-2	2

RefSeq proteins (2): NP_001030022, NP_061873 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR043384	RETREG1/3	Family
IPR055255	RETR1_RHD	Domain
IPR057282	RETREG1-3-like_RHD	Domain

Pfam: PF24456

UniProt features (44 total): mutagenesis site 12, region of interest 6, compositionally biased region 6, topological domain 5, transmembrane region 4, modified residue 3, splice variant 2, sequence variant 2, chain 1, short sequence motif 1, sequence conflict 1, helix 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
7BRQ	X-RAY DIFFRACTION	1.4
7FB5	X-RAY DIFFRACTION	2.84

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9H6L5-F1	59.87	0.00

Functional residue map

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

Post-translational modifications (3): 149, 151, 153

Mutagenesis-validated functional residues (12):

Position	Phenotype
149	reduces self-association.
149	phosphomimetic mutant which enhances self-association. enhanced membrane scission activity; when associated with d-151 a
151	abolishes phosphorylation and reduces self-association.
151	phosphomimetic mutant which enhances self-association. enhanced membrane scission activity; when associated with d-149 a
153	reduces self-association.
153	phosphomimetic mutant which enhances self-association. enhanced membrane scission activity; when associated with d-149 a
453–458	abolishes interaction with atg8 family proteins.
455–458	abolishes interaction with atg8 family proteins and reduces endoplasmic reticulum branching.
456	severely impaired binding to gabarap.
462	severely impaired binding to gabarap.
463	mildly weakened binding to gabarap.
466	mildly weakened binding to gabarap.

Function

Pathways and Gene Ontology

Reactome pathways

1 pathways

ID	Pathway
R-HSA-9920951	Dengue virus modulates apoptosis

MSigDB gene sets: 476 (showing top): GGGACCA_MIR133A_MIR133B, GOBP_NEGATIVE_REGULATION_OF_NEURON_APOPTOTIC_PROCESS, GOBP_VACUOLE_ORGANIZATION, YANG_BREAST_CANCER_ESR1_BULK_UP, GRAESSMANN_APOPTOSIS_BY_DOXORUBICIN_DN, GOBP_WHITE_FAT_CELL_DIFFERENTIATION, MEF2_02, GOBP_MACROAUTOPHAGY, GTGCCTT_MIR506, GOBP_SENSORY_PERCEPTION_OF_PAIN, ONKEN_UVEAL_MELANOMA_UP, WANG_LMO4_TARGETS_DN, SMID_BREAST_CANCER_LUMINAL_B_UP, BILD_E2F3_ONCOGENIC_SIGNATURE, CAIRO_HEPATOBLASTOMA_DN

GO Biological Process (9): mitophagy (GO:0000423), endoplasmic reticulum organization (GO:0007029), sensory perception of pain (GO:0019233), collagen catabolic process (GO:0030574), negative regulation of neuron apoptotic process (GO:0043524), white fat cell differentiation (GO:0050872), reticulophagy (GO:0061709), autophagy (GO:0006914), substrate localization to autophagosome (GO:0061753)

GO Molecular Function (2): endoplasmic reticulum-autophagosome adaptor activity (GO:0140506), protein binding (GO:0005515)

GO Cellular Component (7): nucleolus (GO:0005730), endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), cis-Golgi network (GO:0005801), nuclear body (GO:0016604), Golgi apparatus (GO:0005794), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-1 pathways:

Category	Pathways
Dengue Virus-Host Interactions	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
intracellular membrane-bounded organelle	3
macroautophagy	2
catabolic process	2
intracellular membraneless organelle	2
cytoplasm	2
endomembrane system	2
autophagy of mitochondrion	1
organelle organization	1
endomembrane system organization	1
sensory perception	1
collagen metabolic process	1
negative regulation of apoptotic process	1
regulation of neuron apoptotic process	1
neuron apoptotic process	1
fat cell differentiation	1
transmembrane transport	1
process utilizing autophagic mechanism	1
autophagosome assembly	1
establishment of localization in cell	1
autophagosome-membrane adaptor activity	1
endoplasmic reticulum-organelle membrane tether activity	1
binding	1
nuclear lumen	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
Golgi apparatus	1
nucleoplasm	1
cellular anatomical structure	1

Protein interactions and networks

STRING

1766 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
RETREG1	GABARAP	O95166	952
RETREG1	WNK1	P54963	889
RETREG1	GABARAPL2	P60520	884
RETREG1	SEC62	Q99442	883
RETREG1	RTN3	O95197	823
RETREG1	CCPG1	Q9ULG6	818
RETREG1	ATL3	Q6DD88	814
RETREG1	F5GZY7	F5GZY7	804
RETREG1	CANX	P27824	791
RETREG1	CTNND2	Q9UQB3	785
RETREG1	TEX264	Q9Y6I9	772
RETREG1	CD300C	Q08708	761
RETREG1	NBR1	Q14596	718
RETREG1	SQSTM1	Q13501	661
RETREG1	MAP1LC3B	Q9GZQ8	646

IntAct

14 interactions, top by confidence:

A	B	Type	Score
MAP1LC3A	RETREG1	psi-mi:“MI:0915”(physical association)	0.400
MAP1LC3B	RETREG1	psi-mi:“MI:0915”(physical association)	0.400
GABARAPL1	RETREG1	psi-mi:“MI:0915”(physical association)	0.400
RETREG1	GABARAP	psi-mi:“MI:0915”(physical association)	0.400
RETREG1	BDKRB1	psi-mi:“MI:0915”(physical association)	0.370
RETREG1		psi-mi:“MI:0915”(physical association)	0.370
ARL6IP1	ESYT2	psi-mi:“MI:0914”(association)	0.350
RETREG1	MAP1LC3B2	psi-mi:“MI:0914”(association)	0.350
SLC27A6	NBAS	psi-mi:“MI:0914”(association)	0.350
TMEM216	SNAP23	psi-mi:“MI:2364”(proximity)	0.270
CANX	ESYT2	psi-mi:“MI:2364”(proximity)	0.270
MORC3	RETREG1	psi-mi:“MI:0915”(physical association)	0.000
SNAPIN	RETREG1	psi-mi:“MI:0915”(physical association)	0.000

BioGRID (119): LAPTM4B (Affinity Capture-MS), MAP1LC3B2 (Affinity Capture-MS), FAM134B (Proximity Label-MS), LAPTM4B (Affinity Capture-MS), MAP1LC3B2 (Affinity Capture-MS), FAM134B (Proximity Label-MS), FAM134B (Reconstituted Complex), FAM134B (Proximity Label-MS), MAP1LC3B (Affinity Capture-Western), MAP1LC3B (Co-localization), FAM134B (Two-hybrid), FAM134B (Proximity Label-MS), FAM134B (Proximity Label-MS), FAM134B (Proximity Label-MS), FAM134B (Proximity Label-MS)

ESM2 similar proteins: A1A4V9, A4IFQ0, A6NFY4, A6QNT4, G3HKI1, O60443, P50747, Q13426, Q13769, Q14159, Q1JQA1, Q1RMS8, Q2HJ93, Q2HJB9, Q2KHT6, Q3T1H6, Q3ZK22, Q5E9K8, Q5FVM3, Q5M7Q1, Q5RFG8, Q5RFL7, Q5XI52, Q5ZJK1, Q641X7, Q68FX7, Q6NZQ0, Q6P1K2, Q7YS54, Q7Z6J8, Q8BX13, Q8C5K5, Q8CHQ0, Q8K2I9, Q8NFZ0, Q8QZS3, Q8TCJ0, Q8VE91, Q91WC1, Q91Z62

Diamond homologs: Q0P4Z1, Q3MHU5, Q5E9K8, Q5FVM3, Q6NS82, Q86VR2, Q8NC44, Q8VE91, Q9CQV4, Q9H6L5

SIGNOR signaling

1 interactions.

A	Effect	B	Mechanism
CAMK2B	“up-regulates activity”	RETREG1	phosphorylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 15 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

GO biological processes:

GO term	Partners	Fold	FDR
autophagosome maturation	6	140.4×	1e-10
mitophagy	5	106.0×	3e-08
autophagosome assembly	5	74.9×	1e-07

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	15
Likely pathogenic	5
Uncertain significance	215
Likely benign	131
Benign	39

Top pathogenic / likely-pathogenic (20)

Variant ID	HGVS	Classification
1072083	NC_000005.9:g.(?16483445)(16483591_?)del	Pathogenic
1076405	NM_001034850.3(RETREG1):c.728del (p.Tyr243fs)	Pathogenic
1358533	NM_001034850.3(RETREG1):c.621_622insTTTTTTTTTTTTTTTTTTTTNNNNNNNNNNCTGACCTCATGATCCACCCGCCTCGGCCTCCCTACGTGCTGGGATTACAGGCGTGAGCCACCGCGCCCGGCCGTGTGTGCACATTTTTT (p.Thr208delinsPhePhePhePhePhePheXaaXaaXaaXaaLeuThrSerTer)	Pathogenic
1457038	NM_001034850.3(RETREG1):c.234G>A (p.Trp78Ter)	Pathogenic
1458855	NM_001034850.3(RETREG1):c.413T>A (p.Leu138Ter)	Pathogenic
1903568	NM_001034850.3(RETREG1):c.440G>A (p.Trp147Ter)	Pathogenic
21259	NM_001034850.3(RETREG1):c.873+2T>C	Pathogenic
2738380	NM_001034850.3(RETREG1):c.820_823del (p.Glu274fs)	Pathogenic
328	NM_001034850.3(RETREG1):c.926C>G (p.Ser309Ter)	Pathogenic
330	NM_001034850.3(RETREG1):c.433C>T (p.Gln145Ter)	Pathogenic
3628886	NM_001034850.3(RETREG1):c.549del (p.Glu184fs)	Pathogenic
652106	NM_001034850.3(RETREG1):c.571C>T (p.Gln191Ter)	Pathogenic
835725	NM_001034850.3(RETREG1):c.787C>T (p.Gln263Ter)	Pathogenic
843330	NM_001034850.3(RETREG1):c.321G>A (p.Trp107Ter)	Pathogenic
915376	NM_001034850.3(RETREG1):c.458+2T>C	Pathogenic
1514332	NM_001034850.3(RETREG1):c.320+2T>G	Likely pathogenic
1800429	NM_001034850.3(RETREG1):c.321-2_321delinsTGT	Likely pathogenic
2428731	NM_001034850.3(RETREG1):c.775G>T (p.Glu259Ter)	Likely pathogenic
2788964	NM_001034850.3(RETREG1):c.321-1G>A	Likely pathogenic
4691439	NM_001034850.3(RETREG1):c.427+1G>C	Likely pathogenic

SpliceAI

2489 predictions. Top by Δscore:

Variant	Effect	Δscore
5:16475230:AAGAT:A	acceptor_gain	1.0000
5:16475231:AGAT:A	acceptor_gain	1.0000
5:16475232:GAT:G	acceptor_gain	1.0000
5:16475232:GATC:G	acceptor_loss	1.0000
5:16475233:AT:A	acceptor_gain	1.0000
5:16475234:TC:T	acceptor_loss	1.0000
5:16475235:C:CC	acceptor_gain	1.0000
5:16475235:C:T	acceptor_loss	1.0000
5:16475236:T:C	acceptor_loss	1.0000
5:16475237:G:C	acceptor_gain	1.0000
5:16478844:ACCT:A	donor_loss	1.0000
5:16478845:CCT:C	donor_loss	1.0000
5:16478846:CTA:C	donor_loss	1.0000
5:16478848:A:AC	donor_gain	1.0000
5:16478848:A:AT	donor_loss	1.0000
5:16478849:C:CC	donor_gain	1.0000
5:16478849:C:CT	donor_loss	1.0000
5:16478983:CAGTA:C	acceptor_gain	1.0000
5:16478985:GTA:G	acceptor_gain	1.0000
5:16478988:C:CC	acceptor_gain	1.0000
5:16481089:CAAAA:C	acceptor_gain	1.0000
5:16571990:TCTTA:T	donor_loss	1.0000
5:16571991:CTTA:C	donor_loss	1.0000
5:16571992:TTA:T	donor_loss	1.0000
5:16571993:TAC:T	donor_loss	1.0000
5:16571994:A:AC	donor_gain	1.0000
5:16571994:ACCTC:A	donor_loss	1.0000
5:16571995:C:CC	donor_gain	1.0000
5:16571995:C:CG	donor_loss	1.0000
5:16571995:CCT:C	donor_gain	1.0000

AlphaMissense

3259 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
5:16481073:A:C	S202R	0.997
5:16481073:A:T	S202R	0.997
5:16481075:T:G	S202R	0.997
5:16481091:A:C	F196L	0.996
5:16481091:A:T	F196L	0.996
5:16481093:A:G	F196L	0.996
5:16481019:G:C	S220R	0.995
5:16481019:G:T	S220R	0.995
5:16481021:T:G	S220R	0.995
5:16481078:A:G	C201R	0.995
5:16474870:A:C	F455L	0.994
5:16474870:A:T	F455L	0.994
5:16474872:A:G	F455L	0.994
5:16481069:A:G	C204R	0.994
5:16483364:T:A	K189N	0.994
5:16483364:T:G	K189N	0.994
5:16474871:A:C	F455C	0.993
5:16481090:A:G	C197R	0.991
5:16481092:A:G	F196S	0.991
5:16474847:A:G	L463P	0.990
5:16474862:A:T	L458H	0.990
5:16481047:C:T	G211E	0.989
5:16481048:C:G	G211R	0.988
5:16481048:C:T	G211R	0.988
5:16477705:G:C	F319L	0.987
5:16477705:G:T	F319L	0.987
5:16477707:A:G	F319L	0.987
5:16474865:A:G	L457P	0.985
5:16481065:G:T	T205K	0.983
5:16474871:A:G	F455S	0.982

dbSNP variants (sampled 300 via entrez): RS1000012262 (5:16518369 G>C), RS1000030969 (5:16580765 T>C), RS1000032950 (5:16582576 G>A,C), RS1000041716 (5:16518618 T>A), RS1000050035 (5:16541135 T>C,G), RS1000093963 (5:16589378 G>A,T), RS1000121821 (5:16502706 A>G), RS1000142285 (5:16575976 C>T), RS1000159396 (5:16497675 C>T), RS1000160824 (5:16494094 C>T), RS1000184485 (5:16532511 A>G), RS1000210649 (5:16487638 G>A,T), RS1000278481 (5:16575594 C>A,G), RS1000296963 (5:16500716 CT>C), RS1000314283 (5:16529767 C>G)

Disease associations

OMIM: gene MIM:613114 | disease phenotypes: MIM:303350, MIM:613115, MIM:118220, MIM:201300

GenCC curated gene-disease

Disease	Classification	Inheritance
neuropathy, hereditary sensory and autonomic, type 2B	Definitive	Autosomal recessive
hereditary sensory and autonomic neuropathy type 2	Supportive	Autosomal recessive

ClinGen Gene-Disease Validity (1)

Expert-panel classifications — Definitive > Strong > Moderate > Limited > Disputed > Refuted.

Disease	Classification	Inheritance
hereditary sensory and autonomic neuropathy	Definitive	AR

Mondo (5): hereditary spastic paraplegia (MONDO:0019064), neuropathy, hereditary sensory and autonomic, type 2B (MONDO:0013142), Charcot-Marie-Tooth disease (MONDO:0015626), hereditary sensory and autonomic neuropathy type 2 (MONDO:0019941), neuropathy, hereditary sensory and autonomic, type 2A (MONDO:0024309)

Orphanet (3): Hereditary spastic paraplegia (Orphanet:685), Hereditary sensory and autonomic neuropathy type 2 (Orphanet:970), Charcot-Marie-Tooth disease/Hereditary motor and sensory neuropathy (Orphanet:166)

HPO phenotypes

53 total (30 of 53 shown, HPO-id order):

HPO	Term
HP:0000007	Autosomal recessive inheritance
HP:0000020	Urinary incontinence
HP:0000224	Hypogeusia
HP:0000762	Decreased nerve conduction velocity
HP:0000970	Anhidrosis
HP:0000975	Hyperhidrosis
HP:0001069	Episodic hyperhidrosis
HP:0001182	Tapered finger
HP:0001252	Hypotonia
HP:0001257	Spasticity
HP:0001265	Hyporeflexia
HP:0001284	Areflexia
HP:0001290	Generalized hypotonia
HP:0001810	Dystrophic toenail
HP:0001818	Paronychia
HP:0001842	Foot acroosteolysis
HP:0001870	Acroosteolysis of distal phalanges (feet)
HP:0001939	Abnormality of metabolism/homeostasis
HP:0002020	Gastroesophageal reflux
HP:0002359	Frequent falls
HP:0002645	Wormian bones
HP:0002661	Painless fractures due to injury
HP:0002754	Osteomyelitis
HP:0002797	Osteolysis
HP:0002815	Abnormality of the knee
HP:0002936	Distal sensory impairment
HP:0003028	Abnormality of the ankle
HP:0003103	Abnormal cortical bone morphology
HP:0003202	Skeletal muscle atrophy
HP:0003272	Abnormal hip bone morphology

GWAS associations

5 associations (top):

Study	Trait	p-value
GCST004211_4	Urate levels	2.000000e-08
GCST007637_19	Diffusing capacity of carbon monoxide	9.000000e-06
GCST009391_638	Metabolite levels	1.000000e-06
GCST009936_21	Venous thromboembolism	3.000000e-07
GCST012365_2	Orofacial cleft x maternal periconceptional multivitamin use interaction (1df)	4.000000e-07

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004531	urate measurement
EFO:0009369	diffusing capacity of the lung for carbon monoxide
EFO:0010504	inositol measurement
EFO:0009116	vitamin supplement exposure measurement

MeSH disease descriptors (2)

Descriptor	Name	Tree numbers
D002607	Charcot-Marie-Tooth Disease	C10.500.300.200; C10.574.500.495.200; C10.668.829.800.300.200; C16.131.666.300.200; C16.320.400.375.200
D015419	Spastic Paraplegia, Hereditary	C10.500.300.820; C10.574.500.495.820; C10.668.829.800.300.820; C16.131.666.300.820; C16.320.400.375.820

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

PharmGKB: 1 entry (VIP=true, CPIC=false)

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects expression, affects cotreatment, increases expression	9
Estradiol	decreases reaction, increases expression, affects cotreatment, decreases expression	5
mercuric bromide	affects cotreatment, increases expression	2
Cisplatin	increases expression, affects cotreatment	2
Dexamethasone	increases expression, affects cotreatment	2
Phenylmercuric Acetate	increases expression, affects cotreatment	2
Progesterone	affects cotreatment, decreases expression, increases expression	2
aristolochic acid I	increases expression	1
methylmercuric chloride	decreases expression	1
methyleugenol	decreases expression	1
triphenyl phosphate	affects expression	1
propionaldehyde	increases expression	1
pirinixic acid	increases activity, affects binding, decreases expression	1
trichostatin A	increases expression	1
cobaltous chloride	increases expression	1
potassium chromate(VI)	increases expression	1
ferrous chloride	decreases expression	1
nickel sulfate	increases expression	1
S-(1,2-dichlorovinyl)cysteine	increases expression, affects response to substance	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, increases expression	1
dorsomorphin	increases expression, affects cotreatment	1
bisphenol S	increases methylation	1
jinfukang	affects cotreatment, increases expression	1
Temozolomide	decreases expression	1
Zoledronic Acid	increases expression	1
Acetaminophen	decreases expression	1
Benzo(a)pyrene	decreases expression	1
Carbamazepine	affects expression	1
Doxorubicin	decreases expression	1
Indomethacin	affects cotreatment, increases expression	1

Cellosaurus cell lines

14 cell lines: 12 embryonic stem cell, 2 cancer cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1IC	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/-	Embryonic stem cell	Female
CVCL_D1ID	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- TEX264-/-	Embryonic stem cell	Female
CVCL_D1IE	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- TEX264-/- CCPG1-/-	Embryonic stem cell	Female
CVCL_D1IF	H9 AAVS1-TRE3G-NGN2 RETREG1-/-	Embryonic stem cell	Female
CVCL_D1IM	H9 AAVS1-TRE3G-NGN2 RETREG1-/- Keima-RAMP4	Embryonic stem cell	Female
CVCL_D1IN	H9 AAVS1-TRE3G-NGN2 RETREG1-/- Keima-REEP5	Embryonic stem cell	Female
CVCL_D1IT	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- Keima-RAMP4	Embryonic stem cell	Female
CVCL_D1IU	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- Keima-REEP5	Embryonic stem cell	Female
CVCL_D1IV	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- TEX264-/- Keima-RAMP4	Embryonic stem cell	Female
CVCL_D1IW	H9 AAVS1-TRE3G-NGN2 RETREG3-/- RETREG2-/- RETREG1-/- TEX264-/- Keima-REEP5	Embryonic stem cell	Female

Clinical trials (associated diseases)

108 trials via MONDO — disease-level, not drug-specific.

Trial	Phase	Status	Title
NCT07542548	PHASE4	COMPLETED	D-Cycloserine for Serine Palmitoyltransferase Inhibition
NCT04762758	PHASE3	UNKNOWN	Phase III Trial Assessing the Efficacy and Safety of PXT3003 in CMT1A Patients
NCT03961906	PHASE2	COMPLETED	Physiotherapy in Hereditary Spastic Paraplegia
NCT04768166	PHASE2	COMPLETED	Testing Miglustat Administration in Subjects With Spastic Paraplegia 11
NCT00271635	PHASE2	COMPLETED	Ascorbic Acid Treatment in CMT1A Trial (AATIC)
NCT01401257	PHASE2	COMPLETED	Phase II, Randomized, Placebo-controlled Trial in Patients With Charcot-marie-tooth Disease Type 1A
NCT02561702	PHASE2	COMPLETED	Mexiletine for Muscle Cramps in Charcot Marie Tooth Disease
NCT02967679	PHASE2	COMPLETED	SERENDEM : MD1003 in Patients Suffering From Demyelinating Neuropathies, an Open Label Pilot Study
NCT03124459	PHASE2	TERMINATED	Study of ACE-083 in Patients With Charcot-Marie-Tooth Disease
NCT03254199	PHASE2	TERMINATED	A Study to Assess the Safety and Effectiveness of FLX-787 in Subjects With Charcot-Marie-Tooth Disease Experiencing Muscle Cramps.
NCT03943290	PHASE2	TERMINATED	Extension Study to Evaluate the Long-Term Effects of ACE-083 in Patients With Facioscapulohumeral Muscular Dystrophy (FSHD) and Charcot-Marie Tooth (CMT) Disease Types 1 and X (CMT1 and CMTX)
NCT05777226	PHASE2	UNKNOWN	Research of SORD-CMT Natural History and Epalrestat Treatment
NCT06482437	PHASE2	COMPLETED	Safety and Efficacy of NMD670 in Adult Patients With Type 1 and Type 2 Charcot-Marie-Tooth Disease
NCT06117020	PHASE1	COMPLETED	Single and Multiple Ascending Dose Study of MTR-601 in Healthy Individuals
NCT02604186	PHASE2/PHASE3	COMPLETED	Effects of Botulinum Toxin Injections in Patients With Hereditary Spastic Paraplegia
NCT05518188	PHASE1/PHASE2	RECRUITING	Melpida: Recombinant Adeno-associated Virus (serotype 9) Encoding a Codon Optimized Human AP4M1 Transgene (hAP4M1opt)
NCT06948019	PHASE1/PHASE2	NOT_YET_RECRUITING	Safety and Efficacy of AAV9/AP4B1 (BFB-101) For Patients With AP4B1-related Hereditary Spastic Paraplegia Type 47 (SPG47)
NCT06478238	EARLY_PHASE1	RECRUITING	Calcium Folinate Treatment of Spastic Paraplegia 56
NCT00023075	Not specified	COMPLETED	Nuclear Magnetic Spectroscopy Imaging to Evaluate Primary Lateral Sclerosis, Hereditary Spastic Paraplegia and Amyotrophic Lateral Sclerosis
NCT00136630	Not specified	COMPLETED	Natural History, Genetic Bases and Phenotype-genotype Correlations in Autosomal Dominant Spinocerebellar Degenerations
NCT00140829	Not specified	COMPLETED	SPATAX: Clinical and Genetic Analysis of Cerebellar Ataxias and Spastic Paraplegias
NCT00677768	Not specified	COMPLETED	Validation of Biomarkers in Amyotrophic Lateral Sclerosis (ALS)
NCT01568658	Not specified	ACTIVE_NOT_RECRUITING	Genetic and Physical Study of Childhood Nerve and Muscle Disorders
NCT02327845	Not specified	ENROLLING_BY_INVITATION	Phenotype, Genotype & Biomarkers in ALS and Related Disorders
NCT02852278	Not specified	COMPLETED	A Patient Centric Motor Neuron Disease Activities of Daily Living Scale
NCT02859428	Not specified	TERMINATED	Disease Natural History and Biomarkers of SPG3A, SPG4A, and SPG31
NCT03104088	Not specified	COMPLETED	Studying Cognition in SPG4
NCT03206190	Not specified	RECRUITING	The preSPG4 Study - Studying the Prodromal and Early Phase of SPG4
NCT03627416	Not specified	COMPLETED	Repetitive Transcranial Magnetic Stimulation as Therapy in Hereditary Spastic Paraplegia and Adrenomyeloneuropathy
NCT03981276	Not specified	RECRUITING	Phenotypes, Biomarkers and Pathophysiology in Hereditary Spastic Paraplegias and Related Disorders
NCT04006418	Not specified	RECRUITING	A Registered Cohort Study on Spastic Paraplegia
NCT04180098	Not specified	COMPLETED	Improving Gait Adaptability in Hereditary Spastic Paraplegia
NCT04256681	Not specified	COMPLETED	SNAP: Measurement of the Subjective Perception of the Symptom in Hereditary Spastic Paraparesis (HSP)
NCT04712812	Not specified	RECRUITING	Registry and Natural History Study for Early Onset Hereditary Spastic Paraplegia
NCT04875416	Not specified	ACTIVE_NOT_RECRUITING	Phenotype, Genotype and Biomarkers 2
NCT04912609	Not specified	COMPLETED	Trehalose Administration in Subjects With Spastic Paraplegia 11 (3AL-SPG11)
NCT05354622	Not specified	RECRUITING	Hereditary Spastic Paraplegia Genomic Sequencing Initiative (HSPseq)
NCT05373082	Not specified	COMPLETED	Identification of Modifying Factors in Hereditary Spastic Paraplegia
NCT05411627	Not specified	WITHDRAWN	A Pilot Study of Shockwave Therapy in HSP
NCT05432999	Not specified	COMPLETED	Extracorporeal Shockwave Therapy for Spasticity in People With Spinal Cord Injury