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GeneE
10 sources retrieved Β· Most recent: April 2026 Β· Index updated 14 days ago
β“˜GeneE is for informational purposes only. It is not a substitute for professional medical advice, diagnosis, or treatment.
NSDHL
NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase NSDHL
Chromosome X Β· Xq28
NCBI Gene: 50814Ensembl: ENSG00000147383.12HGNC: HGNC:13398UniProt: A0A384NPZ7
121PubMed Papers
2Diseases
0Drugs
20Pathogenic Variants
FUNCTIONAL ROLE
Highly Constrained
CLINICAL
OMIM Disease Gene
DATA QUALITY
βœ“ Experimental GO Evidenceβœ“ Swiss-Prot Reviewed
endoplasmic reticulum3-beta-hydroxysteroid dehydrogenase [NAD(P)+]/C4-decarboxylase activityprotein bindinglipid dropletCongenital hemidysplasia with ichthyosiform erythroderma and limb defectsCK syndrome
✦AI Summary

NSDHL (NAD(P) dependent 3-beta-hydroxysteroid dehydrogenase) is an X-linked enzyme essential for post-squalene cholesterol biosynthesis, catalyzing the NAD(P)-dependent oxidative decarboxylation of C4 methyl groups in 4-alpha-carboxysterols 1. Beyond its enzymatic role, NSDHL regulates EGFR trafficking and signaling 2. Loss-of-function NSDHL mutations cause CHILD syndrome (congenital hemidysplasia with ichthyosiform erythroderma and limb defects), an X-linked dominant condition typically lethal in males 13. Female carriers present with unilateral ichthyosiform erythroderma and ipsilateral limb abnormalities 45. Clinically, NSDHL dysfunction has emerged as oncologically significant. In pancreatic ductal adenocarcinoma, NSDHL inhibition or cholesterol depletion triggers TGF-Ξ²/epithelial-mesenchymal transition signaling, promoting a basal mesenchymal phenotype associated with poor prognosis 6. Similarly, NSDHL maintains breast cancer stem-like cells through TGF-Ξ²/Smad signaling, with knockdown suppressing tumor-initiating capacity 7. In bladder cancer, the USP43/E2F1/NSDHL pathway regulates cholesterol homeostasis to promote gemcitabine resistance 8. These findings establish NSDHL as a dual-function protein with critical roles in metabolic regulation and cancer stem cell maintenance, positioning it as a therapeutic target for multiple malignancies.

Sources cited
1
NSDHL mutations cause CHILD syndrome and encodes a 3-beta-hydroxysteroid dehydrogenase in cholesterol biosynthesis
PMID: 10710235
2
NSDHL regulates EGFR trafficking and serves as a therapeutic target; NSDHL inhibition suppresses EGFR activity
PMID: 32140747
3
NSDHL mutations cause male lethality in CHILD syndrome and novel variants lead to recurrent male miscarriage
PMID: 36504312
4
NSDHL mutations identified in patients with linear verrucous epidermal nevus, associated with congenital hemidysplasia and limb defects
PMID: 35853659
5
Novel NSDHL missense variant causes CHILD syndrome with syndactyly by impairing steroid dehydrogenase protein function
PMID: 32819291
6
NSDHL loss induces TGF-Ξ² signaling and epithelial-mesenchymal transition in pancreatic cancer, promoting basal phenotype
PMID: 32976774
7
NSDHL maintains breast cancer stem-like cells through TGF-Ξ²/Smad signaling and regulates tumor-initiating capacity
PMID: 39516821
8
NSDHL is activated by E2F1 in the USP43/E2F1/NSDHL pathway to promote gemcitabine resistance via cholesterol homeostasis
PMID: 41437393
Disease Associationsβ“˜2
CK syndromeUniProt
Congenital hemidysplasia with ichthyosiform erythroderma and limb defectsUniProt
Pathogenic Variants20
NM_015922.3(NSDHL):c.317C>T (p.Ser106Leu)Likely pathogenic
Child syndrome|not provided
β˜…β˜†β˜†β˜†2025β†’ Residue 106
NM_015922.3(NSDHL):c.1046A>G (p.Tyr349Cys)Likely pathogenic
Child syndrome|not provided
β˜…β˜†β˜†β˜†2024β†’ Residue 349
NM_015922.3(NSDHL):c.314C>T (p.Ala105Val)Likely pathogenic
Child syndrome|not provided
β˜…β˜†β˜†β˜†2023β†’ Residue 105
NM_015922.3(NSDHL):c.387del (p.Ile129fs)Likely pathogenic
CK syndrome|Child syndrome
β˜…β˜†β˜†β˜†2022β†’ Residue 129
NM_015922.3(NSDHL):c.1098dup (p.Arg367fs)Pathogenic
CK syndrome
β˜…β˜†β˜†β˜†2021β†’ Residue 367
NM_015922.3(NSDHL):c.208C>T (p.Gln70Ter)Pathogenic
not provided
β˜…β˜†β˜†β˜†2020β†’ Residue 70
NM_015922.3(NSDHL):c.267+2T>CLikely pathogenic
not provided|Malignant tumor of urinary bladder
β˜…β˜†β˜†β˜†2020
NM_015922.3(NSDHL):c.683T>G (p.Ile228Ser)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2020β†’ Residue 228
NM_015922.3(NSDHL):c.130G>A (p.Gly44Ser)Likely pathogenic
not provided
β˜…β˜†β˜†β˜†2019β†’ Residue 44
NM_015922.3(NSDHL):c.757C>T (p.Gln253Ter)Pathogenic
Child syndrome
β˜…β˜†β˜†β˜†2014β†’ Residue 253
NM_015922.3(NSDHL):c.1114del (p.Val372fs)Likely pathogenic
Child syndrome
β˜…β˜†β˜†β˜†2013β†’ Residue 372
NM_015922.3(NSDHL):c.1038_1041dup (p.Gly348fs)Pathogenic
Child syndrome
β˜…β˜†β˜†β˜†2013β†’ Residue 348
NM_015922.3(NSDHL):c.906C>A (p.Tyr302Ter)Pathogenic
Child syndrome
β˜…β˜†β˜†β˜†2013β†’ Residue 302
NM_015922.3(NSDHL):c.904del (p.Tyr302fs)Pathogenic
Child syndrome
β˜…β˜†β˜†β˜†2013β†’ Residue 302
NM_015922.3(NSDHL):c.693GAA[1] (p.Lys232del)Pathogenic
CK syndrome
β˜†β˜†β˜†β˜†2010β†’ Residue 232
NM_015922.3(NSDHL):c.451G>T (p.Glu151Ter)Pathogenic
Child syndrome|Thyroid cancer, nonmedullary, 1
β˜†β˜†β˜†β˜†2003β†’ Residue 151
NM_015922.3(NSDHL):c.544G>C (p.Ala182Pro)Pathogenic
Child syndrome
β˜†β˜†β˜†β˜†2002β†’ Residue 182
NM_015922.3(NSDHL):c.628C>T (p.Gln210Ter)Pathogenic
Child syndrome
β˜†β˜†β˜†β˜†2000β†’ Residue 210
NM_015922.3(NSDHL):c.613G>A (p.Gly205Ser)Pathogenic
Child syndrome
β˜†β˜†β˜†β˜†2000β†’ Residue 205
NM_015922.3(NSDHL):c.262C>T (p.Arg88Ter)Pathogenic
Child syndrome
β˜†β˜†β˜†β˜†2000β†’ Residue 88
View on ClinVar β†—
Related Genes
SIGMAR1Protein interaction99%FAXDC2Protein interaction99%ERG28Protein interaction99%FAUProtein interaction95%FDFT1Protein interaction89%LSSProtein interaction89%
Tissue Expression

No tissue expression data available for this gene.

Gene Interaction Network
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NSDHLSIGMAR1FAXDC2ERG28FAUFDFT1LSS
PROTEIN STRUCTURE
Preparing viewer…
PDB6JKG Β· 2.90 Γ… Β· X-ray
View on RCSB β†—
Constraintβ“˜
LOEUFβ“˜
0.21Highly Constrained
pLIβ“˜
1.00Intolerant
Observed/Expected LoF0.04 [0.02–0.21]
RankingsWhere NSDHL stands among ~20K protein-coding genes
  • #3,886of 20,598
    Most Researched121 Β· top quartile
  • #2,188of 5,498
    Most Pathogenic Variants20
  • #487of 17,882
    Most Constrained (LOEUF)0.21 Β· top 5%
Genes detectedNSDHL
Sources retrieved10 papers
Response timeβ€”
πŸ“„ Sources
10β–Ό
1
Cholesterol Pathway Inhibition Induces TGF-Ξ² Signaling to Promote Basal Differentiation in Pancreatic Cancer.
PMID: 32976774
Cancer Cell Β· 2020
1.00
2
Inflammatory linear verrucous epidermal nevus (ILVEN) encompasses a spectrum of inflammatory mosaic disorders.
PMID: 35853659
Pediatr Dermatol Β· 2022
0.90
3
Etiological identification of recurrent male fatality due to a novel NSDHL gene mutation using trio whole-exome sequencing: A rare case report and literature review.
PMID: 36504312
Mol Genet Genomic Med Β· 2023
0.80
4
Crystal structures of human NSDHL and development of its novel inhibitor with the potential to suppress EGFR activity.
PMID: 32140747
Cell Mol Life Sci Β· 2021
0.70
5
Novel variant in NSDHL gene associated with CHILD syndrome and syndactyly- a case report.
PMID: 32819291
BMC Med Genet Β· 2020
0.60