Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia. | LitMetric
St. John's Institute of Dermatology, King's College London (Guy's Campus), London, UK; Centre for Dermatology and Genetic Medicine, Division of Molecular Medicine, University of Dundee, Dundee, UK. Electronic address:
Published: November 2017
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Article Abstract
Mutations in ceramide biosynthesis pathways have been implicated in a few Mendelian disorders of keratinization, although ceramides are known to have key roles in several biological processes in skin and other tissues. Using whole-exome sequencing in four probands with undiagnosed skin hyperkeratosis/ichthyosis, we identified compound heterozygosity for mutations in KDSR, encoding an enzyme in the de novo synthesis pathway of ceramides. Two individuals had hyperkeratosis confined to palms, soles, and anogenital skin, whereas the other two had more severe, generalized harlequin ichthyosis-like skin. Thrombocytopenia was present in all patients. The mutations in KDSR were associated with reduced ceramide levels in skin and impaired platelet function. KDSR enzymatic activity was variably reduced in all patients, resulting in defective acylceramide synthesis. Mutations in KDSR have recently been reported in inherited recessive forms of progressive symmetric erythrokeratoderma, but our study shows that biallelic mutations in KDSR are implicated in an extended spectrum of disorders of keratinization in which thrombocytopenia is also part of the phenotype. Mutations in KDSR cause defective ceramide biosynthesis, underscoring the importance of ceramide and sphingosine synthesis pathways in skin and platelet biology.
Erythrokeratodermia variabilis et progressiva (EKVP) is a rare hereditary skin disorder characterized by hyperkeratotic plaques and erythematous patches that progressively worsen with age. This disorder has been associated with variants in three connexin encoding genes (GJA1, GJB3, GJB4) and four unrelated genes (KRT83, KDSR, TRPM4, PERP). Most cases of connexin-linked EKVP exhibit an autosomal dominant mode of inheritance, with rare autosomal recessive cases.
Erythrokeratodermia variabilis (EKV) is a rare skin disorder marked by red patches and thickened skin plaques, usually inherited in an autosomal dominant pattern.
Traditionally, EKV was linked to mutations in connexin genes, but recent findings show other rare gene mutations can also cause the condition.
A study of seven patients with an EKV-like appearance found they had mutations linked to autosomal recessive congenital ichthyosis (ARCI), suggesting that ARCI should be considered when diagnosing EKV.
Pathogenic variants in the KDSR gene give rise to a Mendelian disorder called PERIOPTER syndrome. The disease is caused by a disruption in ceramide synthesis, with an impact on both skin and bone marrow. Patients with PERIOPTER syndrome show intermittent thrombocytopenia and/or associated anemia as well as disorders of keratinization.
KDSR (3-ketodihydrosphingosine reductase) is a short-chain dehydrogenase located in the endoplasmic reticulum. Mutations in KDSR cause defects in ceramides, which play a key role in the biological processes of the skin and other tissues. Herein, we report a case of compound heterozygous mutations in that caused progressive keratodermia and thrombocytopenia in a 2-year-old male patient.
