KDSR
protein-coding3-ketodihydrosphingosine reductase, the group of Short chain dehydrogenase/reductase superfamily
Gene summary
The protein encoded by this gene catalyzes the reduction of 3-ketodihydrosphingosine to dihydrosphingosine. The putative active site residues of the encoded protein are found on the cytosolic side of the endoplasmic reticulum membrane. A chromosomal rearrangement involving this gene is a cause of follicular lymphoma, also known as type II chronic lymphatic leukemia. The mutation of a conserved residue in the bovine ortholog causes spinal muscular atrophy. [provided by RefSeq, Jul 2008]
- FVT1
MANE transcript
Inheritance
ClinVar variants
Top phenotype
gnomAD constraint
Max pathogenic AF
Genomic locus
External References & Databases
Transcript & Mutation Effects
hg38 • Region Span ~39.5 kbGenCC Phenotypes & Disease Associations
Curated gene-disease validity assertions and inheritance patterns
Inheritance Pattern: AR
Disease ID:MONDO:0033014
Submitter: Genomics England PanelApp
Inheritance Pattern: AD
Disease ID:MONDO:0017851
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0033014
Submitter: G2P
Inheritance Pattern: AD
Disease ID:MONDO:0017851
Submitter: Orphanet
Inheritance Pattern: AR
Disease ID:MONDO:0033014
Submitter: PanelApp Australia
Inheritance Pattern: AR
Disease ID:MONDO:0033014
Submitter: Labcorp Genetics (formerly Invitae)
Inheritance Pattern: AR
Disease ID:MONDO:0033014
Submitter: ClinGen
KDSR is related to inherited disorders of keratinization associated with thrombocytopenia, it was first reported in relation to autosomal recessive erythrokeratodermia variabilis et progressiva 4 in 2017 (Boyden LM, et al., 2017, PMID: 28575652). At least 14 unique variants (e.g. missense, in-frame indel, nonsense, frameshift, and complex rearrangement) have been reported in humans. Evidence supporting this gene-disease relationship included case-level data and experimental data. Variants in this gene have been reported in at least 10 probands in 4 publications (PMIDs: 30467204, 28575652, 31987885, 28774589). Variants in this gene segregated with disease in 1 additional family member. The gene-disease association is supported by its biochemical function as the KDS reductase in the sphingolipid metabolic pathway (PMID: 15328338), the rescue of aberrant size and proplatelet formation in patient megakaryocytes by the WT KDSR transcript in patient-derived induced-megakaryocytes (PMID: 30467204), and a zebrafish model with impaired thrombocyte formation (PMID: 30467204). In summary, KDSR is definitively associated with autosomal recessive erythrokeratodermia variabilis et progressiva 4.
Clinical Genomic Database (CGD)
Manifestation: Dermatologic
Intervention: General
Rationale: Genetic knowledge may be beneficial related to issues such as selection of optimal supportive care, informed medical decision-making, prognostic considerations, and avoidance of unnecessary testing
ClinVar Associated Diseases & Phenotypes
Reported disease conditions connected to KDSR variants in ClinVar
ClinVar Variants & Pathogenicity by Type
Statistics based on transcript NM_002035.4. Only rare variants are included.
We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.
Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.
| Effect | PathogenicP | Likely pathogenicLP | VUS | Likely benignLB | BenignB | Sum |
|---|---|---|---|---|---|---|
| synonymous | 1 | 2 | 2 | 1 | 6 | |
| missense | 1 | 3 | 48 | 1 | 53 | |
| nonsense | 1 | 1 | ||||
| start loss | 0 | |||||
| frameshift | 0 | |||||
| splice donor/acceptor (+/-2bp) | 1 | 1 | 5 | 7 | ||
| Total | 2 | 6 | 55 | 3 | 1 | 67 |
Highest pathogenic variant AF is 0.00006469657
Transcript Catalog
Annotated transcript isoforms across RefSeq and Ensembl databases
| Transcript ID | Source | Protein ID | Coding Exons | MANE Status |
|---|---|---|---|---|
| RefSeq | NP_002026.1 | 10 | MANE Select | |
| Ensembl | ENSP00000494352.1 | 10 | MANE Select | |
| Ensembl | ENSP00000312939.5 | 9 | Standard | |
| Ensembl | ENSP00000312939.5 | 9 | Standard |
Gene Ontology (GO) Annotations & Pathways
Biological processes, molecular functions, cellular components and pathways
Pathways ConsensusPathDB
- Sphingolipid metabolism - Homo sapiens (human)
- Sphingolipid Metabolism
- Gaucher Disease
- Globoid Cell Leukodystrophy
- Metachromatic Leukodystrophy (MLD)
Biological Process
- 3-keto-sphinganine metabolic process
- sphingolipid biosynthetic process
- oxidation-reduction process
Molecular Function
- 3-dehydrosphinganine reductase activity
Cellular Component
- extracellular space
- endoplasmic reticulum
- endoplasmic reticulum membrane
- membrane
- integral component of membrane
gnomAD Constraint
Source:
- Gene type
- protein_coding
- Transcript type
- protein_coding
- Transcript
- ENST00000406396
- Coding exons
- 10
- Length
- 39785
- Individuals with no LoFs
- 125730
- Homozygous LoFs
- 0
- Heterozygous LoFs
- 18
- Defined
- 125748
- p
- 0.0000716
| Z-Score | Observed | Expected | Observed/Expected | Mutation Rate | Total Possible | |
|---|---|---|---|---|---|---|
| Missense | 0.938 | 146 | 182 | 0.804 | 0.00000955 | 2154 |
| Missense (PolyPhen) | 46 | 69.519 | 0.66169 | 719 | ||
| Synonymous | 0.582 | 59 | 65.0 | 0.908 | 0.00000342 | 659 |
| Loss of Function | 2.87 | 5 | 18.2 | 0.275 | 9.32e-7 | 216 |
Population LoF Frequency
| Population | CAF | p-value | Status |
|---|---|---|---|
| African | 0.00012 | 0.00012 | rare |
| Latino/Admixed American | 0.000029 | 0.000029 | rare |
| Ashkenazi Jewish | 0 | 0.0 | absent |
| East Asian | 0 | 0.0 | absent |
| Finnish | 0 | 0.0 | absent |
| European (Non-Finnish) | 0.000098 | 0.000097 | rare |
| South Asian | 0.00010 | 0.000098 | rare |
| Other | 0.00016 | 0.00016 | rare |
dbNSFP Gene Annotations
Source:
- Function
- FUNCTION: Catalyzes the reduction of 3-ketodihydrosphingosine (KDS) to dihydrosphingosine (DHS). {ECO:0000269|PubMed:28575652}.;
- Disease
- DISEASE: Erythrokeratodermia variabilis et progressiva 4 (EKVP4) [MIM:617526]: A form of erythrokeratodermia variabilis et progressiva, a genodermatosis characterized by the coexistence of two independent skin lesions: transient erythema and hyperkeratosis that is usually localized but occasionally occurs in its generalized form. Clinical presentation varies significantly within a family and from one family to another. Palmoplantar keratoderma is present in around 50% of cases. {ECO:0000269|PubMed:28575652}. Note=The disease is caused by mutations affecting the gene represented in this entry.;
Recessive Scores
- pRec
- 0.144
Intolerance Scores
- LoFtool
- 0.306
- RVIS EVS
- -0.14
- RVIS percentile EVS
- 42.88
Essentials
- Essential (CRISPR)
- E
- Essential (CRISPR2)
- E
- Essential (gene trap)
- K
- Indispensability pred.
- E
- Indispensability score
- 0.686
Gene Damage Prediction
| All | Recessive | Dominant | |
|---|---|---|---|
| Mendelian | Medium | Medium | Medium |
| Primary Immunodeficiency | Medium | Medium | Medium |
| Cancer | Medium | Medium | Medium |