NSDHL

Summary

NSDHL (NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHL, HGNC:13398) is a protein-coding gene on chromosome Xq28, encoding Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating (Q15738). Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis. It is haploinsufficient (ClinGen: sufficient evidence).

The protein encoded by this gene is localized in the endoplasmic reticulum and is involved in cholesterol biosynthesis. Mutations in this gene are associated with CHILD syndrome, which is a X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, and typically lethal in males. Alternatively spliced transcript variants with differing 5’ UTR have been found for this gene.

Source: NCBI Gene 50814 — RefSeq curated summary.

At a glance

• Gene–disease (curated): CK syndrome (Definitive, GenCC) — +1 more curated relationship
• Clinical variants (ClinVar): 323 total — 13 pathogenic, 8 likely-pathogenic
• Phenotypes (HPO): 105
• Dosage sensitivity (ClinGen): haploinsufficiency sufficient evidence, triplosensitivity no evidence
• MANE Select transcript: NM_015922

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:13398
Approved symbol	NSDHL
Name	NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHL
Location	Xq28
Locus type	gene with protein product
Status	Approved
Aliases	XAP104, H105e3, SDR31E1
Ensembl gene	ENSG00000147383
Ensembl biotype	protein_coding
OMIM	300275
Entrez	50814

Gene structure

Transcript identifiers

Ensembl transcripts: 28 — 28 protein_coding

ENST00000370274, ENST00000432467, ENST00000440023, ENST00000881875, ENST00000881876, ENST00000881877, ENST00000881878, ENST00000881879, ENST00000881880, ENST00000881881, ENST00000881882, ENST00000881883, ENST00000881884, ENST00000881885, ENST00000881886, ENST00000915680, ENST00000915681, ENST00000915682, ENST00000915683, ENST00000915684, ENST00000915685, ENST00000969426, ENST00000969427, ENST00000969428, ENST00000969429, ENST00000969430, ENST00000969431, ENST00000969432

RefSeq mRNA: 2 — MANE Select: NM_015922 NM_001129765, NM_015922

CCDS: CCDS14717

Canonical transcript exons

ENST00000370274 — 8 exons

Exon	Start	End
ENSE00000979787	152850265	152850423
ENSE00000979788	152858770	152858916
ENSE00000979789	152862596	152862724
ENSE00000979790	152865819	152865961
ENSE00000979791	152867571	152867673
ENSE00001452236	152846282	152846432
ENSE00001937652	152868784	152869729
ENSE00003847136	152831063	152831117

Expression profiles

Bgee: expression breadth ubiquitous, 271 present calls, max score 96.83.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 29.3864 / max 555.7136, expressed in 1813 samples.

FANTOM5 promoters (4 alternative TSS)

Promoter ID	TPM avg	Samples expressed
198010	15.1234	1656
198008	7.5713	1755
198009	6.4043	1744
198007	0.2874	100

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
cervix squamous epithelium	UBERON:0006922	96.83	gold quality
adrenal tissue	UBERON:0018303	95.47	gold quality
esophagus mucosa	UBERON:0002469	92.98	gold quality
endothelial cell	CL:0000115	92.51	gold quality
gingival epithelium	UBERON:0001949	91.90	gold quality
squamous epithelium	UBERON:0006914	91.24	gold quality
right adrenal gland cortex	UBERON:0035827	91.14	gold quality
right adrenal gland	UBERON:0001233	91.13	gold quality
gingiva	UBERON:0001828	90.28	gold quality
lower esophagus mucosa	UBERON:0035834	90.23	gold quality
left adrenal gland	UBERON:0001234	90.09	gold quality
left adrenal gland cortex	UBERON:0035825	90.02	gold quality
adrenal gland	UBERON:0002369	89.95	gold quality
epithelium of esophagus	UBERON:0001976	89.84	gold quality
esophagus squamous epithelium	UBERON:0006920	89.84	gold quality
adrenal cortex	UBERON:0001235	89.59	gold quality
mucosa of transverse colon	UBERON:0004991	89.48	gold quality
ganglionic eminence	UBERON:0004023	89.32	gold quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	88.52	gold quality
right lobe of liver	UBERON:0001114	88.27	gold quality
endometrium epithelium	UBERON:0004811	88.26	silver quality
right atrium auricular region	UBERON:0006631	88.20	gold quality
cortical plate	UBERON:0005343	87.60	gold quality
olfactory segment of nasal mucosa	UBERON:0005386	87.57	gold quality
ventricular zone	UBERON:0003053	87.33	gold quality
cervix epithelium	UBERON:0004801	87.22	gold quality
esophagus	UBERON:0001043	87.03	gold quality
islet of Langerhans	UBERON:0000006	87.01	gold quality
cardiac atrium	UBERON:0002081	86.73	gold quality
tongue squamous epithelium	UBERON:0006919	86.43	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

miRNA regulators (miRDB)

12 targeting NSDHL, 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-1252-5P	100.00	69.80	2774
HSA-MIR-5680	99.91	69.83	3421
HSA-MIR-4663	99.62	65.33	957
HSA-MIR-6758-3P	99.57	67.55	1078
HSA-MIR-6501-3P	98.71	67.45	1480
HSA-MIR-654-3P	98.38	67.61	905
HSA-MIR-1265	98.36	66.46	598
HSA-MIR-3155A	98.16	66.09	965
HSA-MIR-3155B	98.16	66.09	965
HSA-MIR-484	98.16	66.92	1074
HSA-MIR-4632-3P	96.26	58.52	123
HSA-MIR-4798-5P	88.89	63.65	75

Functional genomics

ClinGen dosage: haploinsufficiency 3 (sufficient evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 19)

• NAD(P)H steroid dehydrogenase-like protein is localized to lipid droplets (PMID:12837764)
• NSDHL, an enzyme involved in cholesterol synthesis, traffics through the Golgi and accumulates on ER membranes and on the surface of lipid droplets. (PMID:14506130)
• microarray analysis of gene expression related to NSDHL sterol dehydrogenase in embryonic fibroblasts (PMID:15805545)
• A novel missense mutation (R199H) in exon 6 of the NSDHL gene was identified in a small subset of sporadic verruciform xanthomas. (PMID:16230564)
• NAD(P) dependent steroid dehydrogenase-like (NSDHL)-shRNA sequences were designed and tested for their effectiveness. (PMID:17498944)
• Lethality of Nsdhl deficient mouse embryos is rescued by transgenic mice expressing human Nsdhl. (PMID:19880419)
• The missense mutation of the NSDHL gene is detected in CHILD syndrome. (PMID:19906044)
• found that males with intellectual disability in another reported family with an NSDHL mutation (c.1098 dup [p.Arg367SerfsX33]) have CKS (PMID:21129721)
• human NSDHL protein and mouse Nsdhl mRNA were expressed in tissues synthesizing cholesterol and steroids and in all peripheral tissues affected by CHILD or CK syndromes. (PMID:22113624)
• A novel missense mutation in the NSDHL gene identified in a Lithuanian family by targeted next-generation sequencing causes CK syndrome. (PMID:25900314)
• Our findings expand the spectrum of mutations in NSDHL in CHILD syndrome, and indicate that large exon deletions may be not rare. (PMID:26014843)
• Here we present the case of a 9-year-old Chinese girl born with the typical clinical features of CHILD syndrome. Evaluation of the skin lesions confirmed the diagnosis and led to identification of a heterozygous point mutation in exon 8 of the NSDHL gene. (PMID:26459993)
• NSDHL-containing duplication at chromosome Xq28 inherited from his mother in a male patient with autism spectrum disorder has been reported. (PMID:30376821)
• NSDHL gene mutations associated with CHILD syndrome are common in sporadic oral verruciform xanthoma cases, suggesting that these mutations confer a greater risk for the development of epithelial barrier defects (PMID:31078502)
• Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity. (PMID:32140747)
• NAD(P)-dependent steroid dehydrogenase-like is involved in breast cancer cell growth and metastasis. (PMID:32366230)
• CHILD syndrome in a Malaysian adult with identification of a novel heterozygous missense mutation NSDHL c.602A>G. (PMID:33169834)
• NAD(P)-dependent steroid dehydrogenase-like protein and neutral cholesterol ester hydrolase 1 serve as novel markers for early detection of gastric cancer identified using quantitative proteomics. (PMID:33219617)
• NSDHL promotes triple-negative breast cancer metastasis through the TGFbeta signaling pathway and cholesterol biosynthesis. (PMID:33864166)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	nsdhl	ENSDARG00000099315
mus_musculus	Nsdhl	ENSMUSG00000031349
rattus_norvegicus	Nsdhl	ENSRNOG00000057814
caenorhabditis_elegans		WBGENE00022498
caenorhabditis_elegans		WBGENE00022616

Paralogs (10): TGDS (ENSG00000088451), HSD3B7 (ENSG00000099377), GFUS (ENSG00000104522), GMDS (ENSG00000112699), UXS1 (ENSG00000115652), GALE (ENSG00000117308), SDR42E2 (ENSG00000183921), SDR42E1 (ENSG00000184860), HSD3B1 (ENSG00000203857), HSD3B2 (ENSG00000203859)

Protein

Protein identifiers

Sterol-4-alpha-carboxylate 3-dehydrogenase, decarboxylating — Q15738 (reviewed: Q15738)

Alternative names: Protein H105e3

All UniProt accessions (3): Q15738, A0A384NPZ7, C9JDR0

UniProt curated annotations — full annotation on UniProt →

Function. Catalyzes the NAD(P)(+)-dependent oxidative decarboxylation of the C4 methyl groups of 4-alpha-carboxysterols in post-squalene cholesterol biosynthesis. Also plays a role in the regulation of the endocytic trafficking of EGFR.

Subunit / interactions. Homodimer.

Subcellular location. Endoplasmic reticulum membrane. Lipid droplet.

Tissue specificity. Brain, heart, liver, lung, kidney, skin and placenta.

Disease relevance. Congenital hemidysplasia with ichthyosiform erythroderma and limb defects (CHILD) [MIM:308050] An X-linked dominant disorder of lipid metabolism with disturbed cholesterol biosynthesis, which typically results in male lethality. Clinically, it is characterized by congenital, unilateral, ichthyosisform erythroderma with striking lateralization, sharp midline demarcation, and ipsilateral limb defects and hypoplasia of the body. Limbs defects range from hypoplasia of digits or ribs to complete amelia, often including scoliosis. The disease is caused by variants affecting the gene represented in this entry. CK syndrome (CKS) [MIM:300831] An X-linked recessive disorder characterized by mild to severe cognitive impairment, seizures, microcephaly, cerebral cortical malformations, dysmorphic facial features, and thin body habitus. The disease is caused by variants affecting the gene represented in this entry.

Pathway. Steroid biosynthesis; zymosterol biosynthesis; zymosterol from lanosterol: step 4/6.

Similarity. Belongs to the 3-beta-HSD family.

RefSeq proteins (2): NP_001123237, NP_057006* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR002225	3Beta_OHSteriod_DH/Estase	Domain
IPR036291	NAD(P)-bd_dom_sf	Homologous_superfamily
IPR050177	Lipid_A_modif_metabolic_enz	Family

Pfam: PF01073

Enzyme classification (BRENDA):

• EC 1.1.1.170 — 3beta-hydroxysteroid-4alpha-carboxylate 3-dehydrogenase (decarboxylating) (BRENDA: 5 organisms, 9 substrates, 7 inhibitors, 3 Km, 0 kcat entries)

Substrate kinetics (BRENDA)

2 substrates with measured Km, best-characterized 2. Km ranges are aggregated across organisms/conditions.

Substrate	Km (mM)	Measurements
3BETA-HYDROXY-4BETA-METHYL-5ALPHA-CHOLEST-7-EN-4	0.007	1
3BETA-HYDROXY-CHOLEST-8,24-DIEN-4ALPHA-CARBOXYLA	0.55	1

Catalyzed reactions (Rhea), 10 shown:

• 4beta-methylzymosterol-4alpha-carboxylate + NADP(+) = 3-dehydro-4-methylzymosterol + CO2 + NADPH (RHEA:33447)
• 4alpha-carboxyzymosterol + NADP(+) = zymosterone + CO2 + NADPH (RHEA:33455)
• a 3beta-hydroxysteroid-4alpha-carboxylate + NADP(+) = a 3-oxosteroid + CO2 + NADPH (RHEA:34771)
• a 3beta-hydroxysteroid-4alpha-carboxylate + NAD(+) = a 3-oxosteroid + CO2 + NADH (RHEA:34775)
• 4alpha-carboxy-4beta-methyl-5alpha-cholest-8-en-3beta-ol + NADP(+) = 4alpha-methyl-5alpha-cholest-8-en-3-one + CO2 + NADPH (RHEA:46828)
• 4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol + NADP(+) = 5alpha-cholest-8-en-3-one + CO2 + NADPH (RHEA:46848)
• 4beta-methylzymosterol-4alpha-carboxylate + NAD(+) = 3-dehydro-4-methylzymosterol + CO2 + NADH (RHEA:47160)
• 4alpha-carboxyzymosterol + NAD(+) = zymosterone + CO2 + NADH (RHEA:47164)
• 4alpha-carboxy-4beta-methyl-5alpha-cholest-8-en-3beta-ol + NAD(+) = 4alpha-methyl-5alpha-cholest-8-en-3-one + CO2 + NADH (RHEA:47168)
• 4alpha-carboxy-5alpha-cholest-8-ene-3beta-ol + NAD(+) = 5alpha-cholest-8-en-3-one + CO2 + NADH (RHEA:47172)

UniProt features (34 total): strand 11, helix 9, sequence variant 4, turn 3, modified residue 2, chain 1, transmembrane region 1, short sequence motif 1, active site 1, binding site 1

Structure

Experimental structures (PDB)

2 structures.

PDB	Method	Resolution (Å)
6JKG	X-RAY DIFFRACTION	2.9
6JKH	X-RAY DIFFRACTION	3

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q15738-F1	88.65	0.71

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): 172 (proton acceptor)

Ligand- & substrate-binding residues (1): 176

Post-translational modifications (2): 1, 22

Function

Pathways and Gene Ontology

Reactome pathways

3 pathways

ID	Pathway
R-HSA-6807047	Cholesterol biosynthesis via desmosterol (Bloch pathway)
R-HSA-6807062	Zymostenol biosynthesis via lathosterol (Kandutsch-Russell pathway)
R-HSA-191273	Cholesterol biosynthesis

MSigDB gene sets: 458 (showing top): MORF_MTA1, GOBP_LABYRINTHINE_LAYER_DEVELOPMENT, GOBP_EMBRYO_DEVELOPMENT_ENDING_IN_BIRTH_OR_EGG_HATCHING, GOBP_EPITHELIUM_DEVELOPMENT, MORF_HDAC1, ACEVEDO_NORMAL_TISSUE_ADJACENT_TO_LIVER_TUMOR_DN, IVANOVA_HEMATOPOIESIS_LATE_PROGENITOR, MITSIADES_RESPONSE_TO_APLIDIN_DN, MORF_HDAC2, WEI_MYCN_TARGETS_WITH_E_BOX, GOBP_PLACENTA_BLOOD_VESSEL_DEVELOPMENT, SMITH_TERT_TARGETS_DN, GOMF_STEROID_DEHYDROGENASE_ACTIVITY_ACTING_ON_THE_CH_OH_GROUP_OF_DONORS_NAD_OR_NADP_AS_ACCEPTOR, WANG_ESOPHAGUS_CANCER_VS_NORMAL_DN, GOBP_EMBRYONIC_PLACENTA_DEVELOPMENT

GO Biological Process (10): hair follicle development (GO:0001942), cholesterol biosynthetic process (GO:0006695), smoothened signaling pathway (GO:0007224), cholesterol metabolic process (GO:0008203), obsolete cholesterol biosynthetic process via lathosterol (GO:0033490), labyrinthine layer blood vessel development (GO:0060716), lipid metabolic process (GO:0006629), steroid biosynthetic process (GO:0006694), steroid metabolic process (GO:0008202), sterol biosynthetic process (GO:0016126)

GO Molecular Function (6): 3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity (GO:0000252), 3-beta-hydroxy-Delta5-steroid dehydrogenase (NAD+) activity (GO:0003854), oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor (GO:0016616), 3-beta-hydroxysteroid dehydrogenase (NAD+)/C4-decarboxylase activity (GO:0102175), protein binding (GO:0005515), oxidoreductase activity (GO:0016491)

GO Cellular Component (4): endoplasmic reticulum (GO:0005783), endoplasmic reticulum membrane (GO:0005789), lipid droplet (GO:0005811), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-2 pathways:

Category	Pathways
Cholesterol biosynthesis	2
Metabolism of steroids	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
sterol metabolic process	2
steroid dehydrogenase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor	2
hair cycle process	1
anatomical structure development	1
skin epidermis development	1
cholesterol metabolic process	1
sterol biosynthetic process	1
secondary alcohol biosynthetic process	1
cell surface receptor signaling pathway	1
secondary alcohol metabolic process	1
embryonic organ development	1
placenta blood vessel development	1
labyrinthine layer development	1
primary metabolic process	1
steroid metabolic process	1
lipid biosynthetic process	1
lipid metabolic process	1
steroid biosynthetic process	1
oxidoreductase activity, acting on CH-OH group of donors	1
3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activity	1
binding	1
catalytic activity	1
cytoplasm	1
endomembrane system	1
intracellular membrane-bounded organelle	1
organelle membrane	1
nuclear outer membrane-endoplasmic reticulum membrane network	1
endoplasmic reticulum subcompartment	1
intracellular membraneless organelle	1
cellular anatomical structure	1

Protein interactions and networks

STRING

3258 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
NSDHL	EBP	Q15125	929
NSDHL	SC5D	O75845	909
NSDHL	MSMO1	Q15800	886
NSDHL	CYP51A1	Q16850	857
NSDHL	SQLE	Q14534	856
NSDHL	HSD17B7	P56937	852
NSDHL	FDFT1	P37268	847
NSDHL	DHCR7	Q9UBM7	841
NSDHL	HMGCS1	Q01581	822
NSDHL	GNPAT	O15228	761
NSDHL	DHCR24	Q15392	748
NSDHL	ERG28	Q9UKR5	742
NSDHL	TM7SF2	O76062	736
NSDHL	LSS	P48449	729
NSDHL	MVD	P53602	717

IntAct

102 interactions, top by confidence:

A	B	Type	Score
EXOC1	EXOC5	psi-mi:“MI:0914”(association)	0.730
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
CDS1	CDS2	psi-mi:“MI:0914”(association)	0.670
	NSDHL	psi-mi:“MI:0915”(physical association)	0.560
NSDHL	RHBDD1	psi-mi:“MI:0915”(physical association)	0.560
NSDHL	TMX2	psi-mi:“MI:0915”(physical association)	0.560
NSDHL		psi-mi:“MI:0915”(physical association)	0.560
ATXN1	NSDHL	psi-mi:“MI:0915”(physical association)	0.560
USP47	DENR	psi-mi:“MI:0914”(association)	0.530
SLC31A1	C2orf72	psi-mi:“MI:0914”(association)	0.530
LPAR1	TMEM223	psi-mi:“MI:0914”(association)	0.530
NRAS	ESYT2	psi-mi:“MI:2364”(proximity)	0.480
FAM69C	NSDHL	psi-mi:“MI:0915”(physical association)	0.400
FASN	NSDHL	psi-mi:“MI:0915”(physical association)	0.400
NSDHL	AK4	psi-mi:“MI:0915”(physical association)	0.400
GPC1	SNAP23	psi-mi:“MI:0915”(physical association)	0.400
GPC1	GANAB	psi-mi:“MI:0915”(physical association)	0.400
NSDHL	GPR35	psi-mi:“MI:0915”(physical association)	0.370
FOXB1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXG1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXI2	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL1	DDX39A	psi-mi:“MI:0914”(association)	0.350
FOXL2	DDX39A	psi-mi:“MI:0914”(association)	0.350
NFKB1	NFKB1	psi-mi:“MI:0914”(association)	0.350

BioGRID (206): NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-RNA), NSDHL (Affinity Capture-RNA), NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-MS), NSDHL (Affinity Capture-MS), NSDHL (Proximity Label-MS), NSDHL (Proximity Label-MS), NSDHL (Proximity Label-MS), NSDHL (Proximity Label-MS), NSDHL (Proximity Label-MS), NSDHL (Affinity Capture-MS)

ESM2 similar proteins: A1YER2, A1YFX9, A2T7G9, A6NNS2, B0BN93, B0BNF8, O22718, O35331, O35678, O75911, O77769, O80526, O88876, O95154, P11172, P14755, P15904, P84169, Q06136, Q15738, Q1RMJ5, Q28DS0, Q2KIJ5, Q2QNG7, Q2QZ86, Q3SZM9, Q3T067, Q3ZBE9, Q5E964, Q5I0K3, Q5PPL3, Q5R514, Q5R5C9, Q5RDZ2, Q6AY30, Q6UWP2, Q811X6, Q86WA6, Q8JGT5, Q8K183

Diamond homologs: A0A0B6VQ48, A0A0D1BUI1, A0A1D6P520, A0A1Y0BRF3, A0A2G5ICG8, G3XMB9, G7IYC1, H1ZZB0, O22133, O49163, P14721, P51103, P51105, P51106, P51107, P51108, P51109, Q12068, Q15738, Q3ZBE9, Q500U8, Q54L85, Q5FB34, Q5PPL3, Q5XLY0, Q7PCC4, Q84KP0, Q9R1J0, Q9S9N9, Q9SAH9, Q9UUN9, A6NKP2, A8DZE7, A9X4U2, B2FI29, O35469, O43050, O46516, P0DX24, P14060

SIGNOR signaling

0 interactions.

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 115 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.

Reactome pathways:

Pathway	Partners	Fold	FDR
Translocation of SLC2A4 (GLUT4) to the plasma membrane	5	9.8×	3e-03
COPI-mediated anterograde transport	5	7.0×	6e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	13
Likely pathogenic	8
Uncertain significance	98
Likely benign	53
Benign	36

Top pathogenic / likely-pathogenic (21)

Variant ID	HGVS	Classification
1013083	NM_015922.3(NSDHL):c.208C>T (p.Gln70Ter)	Pathogenic
11427	NM_015922.3(NSDHL):c.613G>A (p.Gly205Ser)	Pathogenic
11428	NM_015922.3(NSDHL):c.628C>T (p.Gln210Ter)	Pathogenic
11429	NM_015922.3(NSDHL):c.262C>T (p.Arg88Ter)	Pathogenic
11430	NM_015922.3(NSDHL):c.544G>C (p.Ala182Pro)	Pathogenic
11431	NM_015922.3(NSDHL):c.451G>T (p.Glu151Ter)	Pathogenic
159454	NM_015922.3(NSDHL):c.757C>T (p.Gln253Ter)	Pathogenic
159456	NM_015922.3(NSDHL):c.904del (p.Tyr302fs)	Pathogenic
159457	NM_015922.3(NSDHL):c.906C>A (p.Tyr302Ter)	Pathogenic
211748	NM_015922.3(NSDHL):c.1038_1041dup (p.Gly348fs)	Pathogenic
21266	NM_015922.3(NSDHL):c.1098dup (p.Arg367fs)	Pathogenic
21268	NM_015922.3(NSDHL):c.693GAA[1] (p.Lys232del)	Pathogenic
4082153	G50R	Pathogenic
1066388	NM_015922.3(NSDHL):c.267+2T>C	Likely pathogenic
11426	NM_015922.3(NSDHL):c.314C>T (p.Ala105Val)	Likely pathogenic
1214891	NM_015922.3(NSDHL):c.683T>G (p.Ile228Ser)	Likely pathogenic
159449	NM_015922.3(NSDHL):c.1114del (p.Val372fs)	Likely pathogenic
21265	NM_015922.3(NSDHL):c.1046A>G (p.Tyr349Cys)	Likely pathogenic
2441794	NM_015922.3(NSDHL):c.387del (p.Ile129fs)	Likely pathogenic
800901	NM_015922.3(NSDHL):c.317C>T (p.Ser106Leu)	Likely pathogenic
958137	NM_015922.3(NSDHL):c.130G>A (p.Gly44Ser)	Likely pathogenic

SpliceAI

1785 predictions. Top by Δscore:

Variant	Effect	Δscore
X:152846280:A:G	acceptor_gain	1.0000
X:152858765:TCCA:T	acceptor_loss	1.0000
X:152858766:CCA:C	acceptor_loss	1.0000
X:152858767:CAGG:C	acceptor_loss	1.0000
X:152858768:A:AT	acceptor_loss	1.0000
X:152858768:AG:A	acceptor_gain	1.0000
X:152858769:GG:G	acceptor_gain	1.0000
X:152858769:GGAT:G	acceptor_gain	1.0000
X:152858912:TTCAG:T	donor_loss	1.0000
X:152858913:TCAGG:T	donor_loss	1.0000
X:152858915:AG:A	donor_loss	1.0000
X:152858916:GG:G	donor_loss	1.0000
X:152858917:GT:G	donor_loss	1.0000
X:152858918:T:G	donor_loss	1.0000
X:152862579:T:TA	acceptor_gain	1.0000
X:152862721:GAGG:G	donor_gain	1.0000
X:152865818:GGCA:G	acceptor_gain	1.0000
X:152865959:TGGG:T	donor_loss	1.0000
X:152865960:GG:G	donor_gain	1.0000
X:152865960:GGGT:G	donor_loss	1.0000
X:152865961:GG:G	donor_gain	1.0000
X:152865961:GGTG:G	donor_loss	1.0000
X:152865962:G:C	donor_loss	1.0000
X:152865962:G:GG	donor_gain	1.0000
X:152865963:TGAG:T	donor_loss	1.0000
X:152867560:T:TA	acceptor_gain	1.0000
X:152867566:TGCAG:T	acceptor_loss	1.0000
X:152867568:CAG:C	acceptor_loss	1.0000
X:152867569:A:AG	acceptor_gain	1.0000
X:152867569:AGA:A	acceptor_loss	1.0000

AlphaMissense

2460 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
X:152862611:A:C	S144R	0.998
X:152862613:C:A	S144R	0.998
X:152862613:C:G	S144R	0.998
X:152862614:A:C	S145R	0.997
X:152862616:T:A	S145R	0.997
X:152862616:T:G	S145R	0.997
X:152862709:G:C	K176N	0.997
X:152862709:G:T	K176N	0.997
X:152865870:C:A	R199S	0.996
X:152865871:G:C	R199P	0.996
X:152858898:C:G	C132W	0.995
X:152862620:A:C	S147R	0.995
X:152862622:T:A	S147R	0.995
X:152862622:T:G	S147R	0.995
X:152850298:T:C	F48L	0.994
X:152850300:C:A	F48L	0.994
X:152850300:C:G	F48L	0.994
X:152858804:T:A	V101D	0.994
X:152858865:T:A	N121K	0.994
X:152858865:T:G	N121K	0.994
X:152862612:G:T	S144I	0.994
X:152865870:C:G	R199G	0.994
X:152867610:C:A	N242K	0.994
X:152867610:C:G	N242K	0.994
X:152858807:T:C	F102S	0.993
X:152858897:G:A	C132Y	0.993
X:152868980:T:A	V329D	0.992
X:152858873:G:A	G124D	0.991
X:152858896:T:C	C132R	0.991
X:152862600:T:C	L140P	0.991

dbSNP variants (sampled 300 via entrez): RS1000011785 (X:152856969 C>T), RS1000109183 (X:152834712 A>G), RS1000191531 (X:152848893 C>T), RS1000307677 (X:152849423 G>A), RS1000558690 (X:152829957 T>C), RS1000799500 (X:152864193 G>A), RS1000915618 (X:152864491 C>T), RS1001136482 (X:152855642 C>G), RS1001201552 (X:152858171 G>A), RS1001253518 (X:152857808 G>A), RS1001367074 (X:152849598 C>A), RS1001835163 (X:152830793 C>T), RS1001881875 (X:152850022 C>A,T), RS1002119269 (X:152830638 C>T), RS1002432789 (X:152847792 A>G)

Disease associations

OMIM: gene MIM:300275 | disease phenotypes: MIM:300831, MIM:308050

GenCC curated gene-disease

Disease	Classification	Inheritance
CHILD syndrome	Definitive	X-linked
CK syndrome	Definitive	X-linked

ClinGen Gene-Disease Validity (1)

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

Disease	Classification	Inheritance
CK syndrome	Moderate	XL

Mondo (8): CK syndrome (MONDO:0010441), CHILD syndrome (MONDO:0010621), intellectual disability (MONDO:0001071), connective tissue disorder (MONDO:0003900), mitral valve prolapse (MONDO:0004910), hearing loss disorder (MONDO:0005365), scoliosis (MONDO:0005392), unilateral polymicrogyria (MONDO:0017092)

Orphanet (4): CHILD syndrome (Orphanet:139), CK syndrome (Orphanet:251383), Unilateral polymicrogyria (Orphanet:268943), NON RARE IN EUROPE: Unexplained intellectual disability (Orphanet:319658)

HPO phenotypes

105 total (30 of 105 shown, HPO-id order):

HPO	Term
HP:0000104	Renal agenesis
HP:0000122	Unilateral renal agenesis
HP:0000126	Hydronephrosis
HP:0000204	Cleft upper lip
HP:0000218	High palate
HP:0000252	Microcephaly
HP:0000272	Malar flattening
HP:0000275	Narrow face
HP:0000276	Long face
HP:0000278	Retrognathia
HP:0000286	Epicanthus
HP:0000308	Microretrognathia
HP:0000347	Micrognathia
HP:0000358	Posteriorly rotated ears
HP:0000365	Hearing impairment
HP:0000426	Prominent nasal bridge
HP:0000486	Strabismus
HP:0000582	Upslanted palpebral fissure
HP:0000678	Dental crowding
HP:0000708	Atypical behavior
HP:0000718	Aggressive behavior
HP:0000737	Irritability
HP:0000750	Delayed speech and language development
HP:0000752	Hyperactivity
HP:0000773	Short ribs
HP:0000835	Adrenal hypoplasia
HP:0000882	Hypoplastic scapulae
HP:0000894	Short clavicles
HP:0000954	Single transverse palmar crease
HP:0000962	Hyperkeratosis

GWAS associations

0 associations (top):

MeSH disease descriptors (6)

Descriptor	Name	Tree numbers
D003240	Connective Tissue Diseases	C17.300
D034381	Hearing Loss	C09.218.458.341; C10.597.751.418.341; C23.888.592.763.393.341
D008607	Intellectual Disability	C10.597.606.360; C23.888.592.604.646; F01.700.687; F03.625.539
D008945	Mitral Valve Prolapse	C14.280.484.400.500
D012600	Scoliosis	C05.116.900.800.875
C562515	Congenital Hemidysplasia with Ichthyosiform Erythroderma and Limb Defects (supp.)

Drugs & pharmacology

Drug and pharmacology data

Is drug target: no

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

GtoPdb / IUPHAR curated pharmacology

(IUPHAR/BPS Guide to Pharmacology — expert-curated)

Target class: enzyme — Cholesterol biosynthesis pathway

Most potent curated ligand interactions (1 total), top 1:

Ligand	Action	Affinity	Parameter
compound 9 [PMID: 32140747]	Binding	5.63	pKd

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, increases expression, affects expression, decreases expression, decreases methylation	5
perfluorooctane sulfonic acid	decreases expression	3
Cyclosporine	decreases expression, affects cotreatment, affects expression	3
Particulate Matter	increases expression, affects cotreatment, decreases expression, increases abundance	3
bisphenol A	affects expression, increases expression	2
perfluorooctanoic acid	increases expression	2
Arsenic Trioxide	affects binding, decreases reaction, decreases expression	2
Benzo(a)pyrene	affects methylation, decreases expression	2
Aflatoxin B1	affects expression, decreases expression	2
Copper Sulfate	decreases expression, increases expression	2
22-hydroxycholesterol	decreases expression	1
methyleugenol	decreases expression	1
deoxynivalenol	decreases expression	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, increases expression	1
beta-lapachone	decreases expression, increases expression	1
sodium arsenite	decreases expression	1
potassium chromate(VI)	decreases expression	1
aflatoxin B2	decreases methylation	1
4-aminophenylarsenoxide	affects binding, decreases reaction	1
di-n-butylphosphoric acid	affects expression	1
yessotoxin	increases expression	1
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one	decreases response to substance	1
perfluoro-n-nonanoic acid	decreases expression	1
epoxiconazole	increases expression	1
monomethylarsonous acid	decreases expression	1
K 7174	decreases expression	1
bisphenol B	increases expression	1
abrine	decreases expression, increases expression	1
2,2’,4,4’-tetrabromodiphenyl ether	affects expression	1
archazolid B	increases expression	1

Cellosaurus cell lines

1 cell lines: 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_B3CU	Abcam HEK293T NSDHL KO	Transformed cell line	Female

Clinical trials (associated diseases)

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

Trial	Phase	Status	Title
NCT05657860	PHASE4	COMPLETED	Guanfacine Extended Release for the Reduction of Aggression and Self-injurious Behavior Associated With Prader-Willi Syndrome
NCT05744479	PHASE4	RECRUITING	Metformin for Antipsychotic-induced Weight Gain in Adults With Intellectual Disability
NCT06107829	PHASE4	WITHDRAWN	Valbenazine Treatment of Tardive Dyskinesia in Adults With Intellectual/Developmental Disabilities
NCT06997198	PHASE4	NOT_YET_RECRUITING	Deutetrabenazine Treatment for Tardive Dyskinesia in Intellectual/Developmental Disabilities
NCT01042158	PHASE4	COMPLETED	A Clinical Trial of Ambrisentan and Tadalafil in Pulmonary Arterial Hypertension Associated With Systemic Sclerosis
NCT03688191	PHASE4	UNKNOWN	Study of Sirolimus in CTD-TP in China
NCT04169100	PHASE4	UNKNOWN	Novel Form of Acquired Long QT Syndrome
NCT04197050	PHASE4	UNKNOWN	Effect of Sacubitril/Valsartan on Reduced Right Ventricular Ejection Fraction in Patients With CTD
NCT04928586	PHASE4	UNKNOWN	Immunosuppressant Combined With Pirfenidone in CTD-ILD
NCT05440240	PHASE4	RECRUITING	Percutaneous Needle Fasciotomy +/- Corticosteroid Injection for Dupuytren’s Contracture
NCT05505409	PHASE4	UNKNOWN	Efficacy and Safety of Pirfenidone in CTD-ILD
NCT06499233	PHASE4	RECRUITING	Efficacy and Safety of Prophylactic Treatment for Pneumocystis Jirovecii Pneumonia in Patients With Autoimmune Inflammatory Rheumatic Disease
NCT02270736	PHASE3	COMPLETED	Clinical Study to Investigate the Efficacy and Safety of NT 201 Compared to Placebo in the Treatment of Chronic Troublesome Drooling Associated With Neurological Disorders and/or Intellectual Disability
NCT00864201	PHASE3	UNKNOWN	A Study to Evaluate the Use of Bosentan in Patients With Exercise Induced Pulmonary Arterial Hypertension Associated With Connective Tissue Disease
NCT01196091	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01205438	PHASE3	COMPLETED	A Study of LY2127399 in Participants With Systemic Lupus Erythematosus
NCT01488708	PHASE3	TERMINATED	On Open-Label Study in Participants With Systemic Lupus Erythematosus
NCT03626688	PHASE3	COMPLETED	A Study Evaluating the Efficacy and Safety of Ralinepag to Improve Treatment Outcomes in PAH Patients
NCT03683186	PHASE3	ENROLLING_BY_INVITATION	A Study Evaluating the Long-Term Efficacy and Safety of Ralinepag in Subjects With PAH Via an Open-Label Extension
NCT04084678	PHASE3	TERMINATED	A Study of Ralinepag to Evaluate Effects on Exercise Capacity by CPET in Subjects With WHO Group 1 PH
NCT06716606	PHASE3	RECRUITING	A Study to Investigate the Long-term Safety and Efficacy of Belimumab in Adults With Interstitial Lung Disease (ILD) Associated With Systemic Sclerosis (SSc) and Other Connective Tissue Diseases (CTD) (BLISSconneCTD-OLE)
NCT06917690	PHASE3	RECRUITING	A Study to Learn About the Safety and Efficacy of the Drug Oleogel-S10 in Japanese Patients With Epidermolysis Bullosa
NCT01110642	PHASE2	WITHDRAWN	Novel Treatment for Syndromic Ichthyoses
NCT02304302	PHASE2	COMPLETED	Down Syndrome Memantine Follow-up Study
NCT03862950	PHASE2	COMPLETED	A Trial of Metformin in Individuals With Fragile X Syndrome (Met)
NCT04529226	PHASE2	UNKNOWN	Study to Compare Clozapine vs Treatment as Usual in People With Intellectual Disability & Treatment-resistant Psychosis
NCT04821856	PHASE2	COMPLETED	Evaluation of the Effectiveness of Cannabidiol in Treating Severe Behavioural Problems in Children and Adolescents With Intellectual Disability
NCT00004357	PHASE2	COMPLETED	Absorption of Corticosteroids in Children With Juvenile Dermatomyositis
NCT00005675	PHASE2	COMPLETED	Oral Type I Collagen for Relieving Scleroderma
NCT01808196	PHASE2	COMPLETED	Testing Effectiveness of Losartan in Patients With EoE With or Without a CTD
NCT02682511	PHASE2	ACTIVE_NOT_RECRUITING	Oral Ifetroban to Treat Diffuse Cutaneous Systemic Sclerosis (SSc) or SSc-associated Pulmonary Arterial Hypertension
NCT04993885	PHASE2	RECRUITING	Avatrombopag in the Treatment of Adult Immune Thrombocytopenia With Autoantibodies
NCT05516758	PHASE2	TERMINATED	A Study of Peresolimab (LY3462817) in Participants With Moderately-to-Severely Active Rheumatoid Arthritis
NCT05998759	PHASE2	RECRUITING	Telitacicept for the Treatment of Connective Tissue Disease-associated Thrombocytopenia
NCT06104228	PHASE2	RECRUITING	129 Xenon MRI as a Biomarker for Diagnosis and Response to Therapy in Pulmonary Arterial Hypertension (PAH)
NCT05273320	PHASE1	COMPLETED	Clinical Trial of Nabilone for Aggression in Adults With Intellectual and Developmental Disabilities
NCT05301361	PHASE1	ENROLLING_BY_INVITATION	Sensitivity of the NIH Toolbox to Stimulant Treatment in Intellectual Disabilities
NCT06016764	PHASE1	COMPLETED	Use of MRI and cTBS for Catatonia in Autism
NCT06586827	PHASE1	COMPLETED	Impact of Competency-Based Training and Technical Assistance Employment Outcomes of Individuals With ID/DD
NCT07531940	PHASE1	NOT_YET_RECRUITING	Escalating Doses of Memantine in Down Syndrome (MEDS-123)