Alternative titles; symbols
HGNC Approved Gene Symbol: KDSR
Cytogenetic location: 18q21.33 Genomic coordinates (GRCh38): 18:63,327,726-63,367,206 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.33 | Erythrokeratodermia variabilis et progressiva 4 | 617526 | Autosomal recessive | 3 |
Sphingolipids are essential lipid components of the plasma membrane. Together with cholesterol, sphingolipids form lipid microdomains or rafts that are involved in membrane traffic and cell signaling. Synthesis of sphingolipids initiates with condensation of L-serine with palmitoyl-CoA, producing 3-ketodihydrosphingosine (KDS), followed by reduction to dihydrosphingosine by KDS reductases, like FVT1 (Kihara and Igarashi, 2004).
The variant t(2;18) and t(18;22) chromosome translocations observed in B-cell chronic lymphocytic leukemias (see 151400) and in follicular lymphomas consistently involve the 5-prime region of the BCL2 gene (151430) on chromosome 18 and various regions of the Ig light chain loci, either kappa (147200) on chromosome 2 or lambda (147220) on chromosome 22. These are variant translocations in these disorders because the finding in a large proportion of non-Hodgkin B-cell lymphomas, usually of follicular type, is the t(14;18)(q32;q21) translocation. Rimokh et al. (1993) showed that a variant t(2;18) translocation observed in a case of follicular lymphoma led to the juxtaposition of a J-kappa segment to a chromosome 18 transcriptional unit located 10 kb upstream of the BCL2 locus. The cDNA of this evolutionarily conserved gene, termed FVT1 for follicular-variant-translocation gene, encodes a putative secreted protein of 36 kD. FVT1 was weakly expressed in all normal hematopoietic tissues tested, but showed a very high rate of transcription in some T-cell malignancies and in phytohemagglutinin-stimulated lymphocytes. Rimokh et al. (1993) suggested that in light of the proximity of FVT1 to BCL2, both genes may participate in the tumoral process.
By searching for sequences similar to the yeast KDS reductase, Tsc10, followed by PCR of a liver cDNA library, Kihara and Igarashi (2004) cloned FVT1. The deduced 332-amino acid protein contains an N-terminal transmembrane segment, followed by a large hydrophilic domain, 2 C-terminal transmembrane segments, and a KKxx-type endoplasmic reticulum (ER) retention signal at its C terminus. The hydrophilic domain shows characteristics of a short-chain dehydrogenase/reductase. Mouse Fvt1 shares 92.8% amino acid identity with human FVT1. Northern blot analysis detected 2.7- and 2.5-kb FVT1 transcripts in all human tissues examined. FVT1 expression was highest in skeletal muscle and heart and lowest in colon, thymus, and peripheral blood leukocytes. The 2.5-kb transcript predominated in all tissues examined except placenta. A 1.3-kb transcript was also detected in heart and skeletal muscle. Immunofluorescence microscopy revealed coexpression of FVT1 with an ER marker in FVT1-transfected HeLa cells.
Kihara and Igarashi (2004) found that expression of mouse or human FVT1 suppressed growth defects in Tsc10-null yeast. FVT1 overexpressed in cultured human cells exhibited KDS reductase activity in vitro, and purified recombinant FVT1 exhibited NADPH-dependent KDS reductase activity. Proteinase K digestion assays revealed that the large hydrophilic catalytic domain of FVT1 localized to the cytosolic face of ER membranes. Kihara and Igarashi (2004) concluded that FVT1 converts KDS to dihydrosphingosine in the cytosolic side of the ER membrane.
In 4 unrelated patients with erythrokeratodermia variabilis et progressiva-4 (EKVP4; 617526), Boyden et al. (2017) identified compound heterozygosity for variants in the KDSR gene (136440.0001-136440.0004). In 2 of the patients, the second variant was a 346-kb inversion on chromosome 18 that replaces the upstream promoter, 5-prime UTR, start codon, and first 2 exons of the KDSR gene with unrelated sequence.
In a female patient (kindred 429) with erythrokeratodermia variabilis et progressiva-4 (EKVP4; 617526), Boyden et al. (2017) identified compound heterozygosity for mutations in the KDSR gene: a 3-bp deletion (c.164_166AAG, NM_002035.2) in exon 2, resulting in Gln55_Gly56delinsArg within the hydrophilic enzymatic domain, and a c.879G-A transition at the last base of exon 9, resulting in a gln293-to-gln (Q293Q; 136440.0003) silent substitution. The proband's unaffected parents were each heterozygous for one of the mutations. Because the guanine involved in the silent mutation in exon 9 is highly conserved and might alter splicing, the authors examined KDSR transcripts from patient skin tissue, which revealed an in-frame deletion of exon 9 (Gln260_Gln293del). Studies in yeast null for the orthologous yeast KDS reductase, Tsc10, demonstrated that wildtype KDSR complemented the depletion of endogenous Tsc10, whereas both mutant forms of KDSR failed to complement.
In a female patient (kindred 101) with erythrokeratodermia variabilis et progressiva-4 (EKVP4; 617526), Boyden et al. (2017) identified compound heterozygosity for mutations in the KDSR gene: a splice site mutation (c.256-2A-C, NM_002035.2) in intron 3, and a c.879G-A transition, resulting in a gln293-to-gln (Q293Q; 136440.0003) silent substitution that was shown to cause an in-frame deletion of exon 9 (Gln260_Gln293del). The proband's unaffected parents were each heterozygous for one of the mutations. RT-PCR in transfected HEK293 cells revealed that the c.256-2A-C splice site mutation causes an in-frame deletion of exon 4 (Val86_Gln107del) involving the NAD-binding domain within the hydrophilic enzymatic domain. Studies in yeast null for the orthologous yeast KDS reductase, Tsc10, demonstrated that wildtype KDSR complemented the depletion of endogenous Tsc10, whereas both mutant forms of KDSR failed to complement.
In a male patient (kindred 1107) with erythrokeratodermia variabilis et progressiva-4 (EKVP4; 617526), Boyden et al. (2017) identified compound heterozygosity for mutations in the KDSR gene: a c.879G-A transition (c.879G-A, NM_002035.2) at the last base of exon 9, resulting in a gln293-to-gln (Q293Q) silent substitution that was shown to cause an in-frame deletion of exon 9 (Gln260_Gln293del) involving both the homodimer and homotetramer interfaces within the hydrophilic enzymatic domain, and a 346-kb inversion on chromosome 18 (g.63,361,789_63,707,612inv, GRCh38) that replaces the upstream promoter, 5-prime UTR, start codon, and first 2 exons of the KDSR gene with unrelated sequence, abolishing expression of KDSR. The proband's unaffected parents were each heterozygous for one of the mutations. The Q293Q mutation was also identified in compound heterozygosity with other KDSR mutations (136440.0001; 136440.0002) in 2 patients with EKVP4. Immunostaining of tissue from proband 1107 showed normal KDSR intensity and localization, and distributions of KRT10 (148080) and KRT14 (148066) were normal. However, despite histologic absence of a granular layer, affected tissue showed expansion of filaggrin (135940) immunostaining. Boyden et al. (2017) stated that these results suggested a defect in keratinocyte terminal differentiation. Studies in yeast null for the orthologous yeast KDS reductase, Tsc10, demonstrated that wildtype KDSR complemented the depletion of endogenous Tsc10, whereas the Gln260_Gln293del mutant KDSR failed to complement.
In a female patient (kindred 438) with erythrokeratodermia variabilis et progressiva-4 (EKVP4; 617526), Boyden et al. (2017) identified compound heterozygosity for mutations in the KDSR gene: a c.557A-T transversion (c.557A-T, NM_002035.2) in exon 6, resulting in a tyr186-to-phe (Y186F) substitution at a highly conserved active-site tyrosine, and a 346-kb inversion on chromosome 18 (g.63,361,789_63,707,612inv, GRCh38) that replaces the upstream promoter, 5-prime UTR, start codon, and first 2 exons of the KDSR gene with unrelated sequence, abolishing expression of KDSR. The proband's unaffected parents were each heterozygous for one of the mutations.
Boyden, L. M., Vincent, N. G., Zhou, J., Hu, R., Craiglow, B. G., Bayliss, S. J., Rosman, I. S., Lucky, A. W., Diaz, L. A., Goldsmith, L. A., Paller, A. S., Lifton, R. P., Baserga, S. J., Choate, K. A. Mutations in KDSR cause recessive progressive symmetric erythrokeratoderma. Am. J. Hum. Genet. 100: 978-984, 2017. [PubMed: 28575652] [Full Text: https://doi.org/10.1016/j.ajhg.2017.05.003]
Kihara, A., Igarashi, Y. FVT-1 is a mammalian 3-ketodihydrosphingosine reductase with an active site that faces the cytosolic side of the endoplasmic reticulum membrane. J. Biol. Chem. 279: 49243-49250, 2004. [PubMed: 15328338] [Full Text: https://doi.org/10.1074/jbc.M405915200]
Rimokh, R., Gadoux, M., Bertheas, M.-F., Berger, F., Garoscio, M., Deleage, G., Germain, D., Magaud, J.-P. FVT-1, a novel human transcription unit affected by variant translocation t(2;18)(p11;q21) of follicular lymphoma. Blood 81: 136-142, 1993. [PubMed: 8417785]