KDSR (3-Ketodihydrosphingosine Reductase)
Key enzyme in de novo sphingolipid biosynthesis; mutations cause keratoderma and neurological disorders
Gene Information Card
| Symbol | KDSR |
|---|---|
| Full Name | 3-ketodihydrosphingosine reductase |
| Gene Type | Protein-coding |
| Chromosomal Location | 18q21.33 |
| NCBI Gene ID | 2531 ncbi.nlm.nih.gov/gene/2531 |
| Ensembl ID | ENSG00000101680 |
| UniProt ID | Q06136 |
| OMIM ID | 136440 |
| HGNC ID | 6240 |
| Aliases | FVT1, SDR35C1, DHSR, SDR35C2 |
Description
KDSR encodes 3-ketodihydrosphingosine reductase, an enzyme in the short-chain dehydrogenase/reductase (SDR) family. It catalyzes the NADPH-dependent reduction of 3-ketodihydrosphingosine to dihydrosphingosine, a critical step in de novo sphingolipid biosynthesis. Sphingolipids are essential components of cell membranes and signaling molecules. Mutations in KDSR are associated with autosomal recessive keratoderma with neurologic involvement and erythrokeratodermia variabilis et progressiva.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Keratoderma with neurologic involvement | Loss-of-function mutations impair sphingolipid synthesis, leading to abnormal skin barrier and neurodegeneration | PMID: 28132693, ClinVar |
| Erythrokeratodermia variabilis et progressiva | Missense mutations reduce enzyme activity, disrupting epidermal lipid homeostasis | PMID: 28132693, OMIM #136440 |
| Sphingolipid deficiency syndrome | Biallelic KDSR mutations cause severe deficiency of complex sphingolipids | PMID: 28132693 |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Skin | 15.2 | Medium |
| Liver | 12.8 | Medium |
| Brain | 8.5 | Low |
| Kidney | 10.1 | Medium |
| Lung | 7.3 | Low |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HaCaT (keratinocytes) | 18.4 | High expression in skin-derived cells |
| HepG2 | 14.1 | Moderate expression |
| SH-SY5Y | 6.2 | Low expression |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.574C>T (p.Arg192Trp) | Missense | Rare | Reduced enzyme activity; associated with keratoderma |
| c.1A>G (p.Met1Val) | Start loss | Very rare | Complete loss of function; severe phenotype |
| c.832G>A (p.Gly278Arg) | Missense | Rare | Impaired NADPH binding; erythrokeratodermia |
Mutation functional classification
Loss of Function (LOF)
Biallelic loss-of-function mutations (e.g., start loss, nonsense) cause severe sphingolipid deficiency and multisystem disease.
Gain of Function (GOF)
No gain-of-function mutations reported.
Dominant Negative (DN)
No dominant-negative mutations reported; all pathogenic variants are recessive.
View complete mutation data：
Gene Ontology (GO)
| • 3-ketodihydrosphingosine reductase activity (GO:0003854) | • sphingolipid biosynthetic process (GO:0006665) |
| • oxidoreductase activity (GO:0016491) | • endoplasmic reticulum (GO:0005783) |
Pathways
• Sphingolipid metabolism (KEGG: hsa00600)
• De novo sphingolipid biosynthesis (Reactome: R-HSA-1660661)
Protein Summary
The KDSR protein (UniProt Q06136) is a 342-amino acid transmembrane enzyme localized to the endoplasmic reticulum. It belongs to the short-chain dehydrogenase/reductase (SDR) family and contains a conserved NADPH-binding domain. The enzyme reduces 3-ketodihydrosphingosine to dihydrosphingosine, the precursor for ceramide and complex sphingolipids. Defects in KDSR lead to accumulation of toxic sphingoid bases and impaired skin barrier function.
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