RT Journal Article
T1 Biallelic Mutations in KDSR Disrupt Ceramide Synthesis and Result in a Spectrum of Keratinization Disorders Associated with Thrombocytopenia.
A1 Takeichi, Takuya
A1 Torrelo, Antonio
A1 Lee, John Y W
A1 Ohno, Yusuke
A1 Lozano, María Luisa
A1 Kihara, Akio
A1 Liu, Lu
A1 Yasuda, Yuka
A1 Ishikawa, Junko
A1 Murase, Takatoshi
A1 Rodrigo, Ana Belén
A1 Fernández-Crehuet, Pablo
A1 Toi, Yoichiro
A1 Mellerio, Jemima
A1 Rivera, José
A1 Vicente, Vicente
A1 Kelsell, David P
A1 Nishimura, Yutaka
A1 Okuno, Yusuke
A1 Kojima, Daiei
A1 Ogawa, Yasushi
A1 Sugiura, Kazumitsu
A1 Simpson, Michael A
A1 McLean, W H Irwin
A1 Akiyama, Masashi
A1 McGrath, John A
AB 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.
YR 2017
FD 2017-07-31
LK http://hdl.handle.net/10668/11472
UL http://hdl.handle.net/10668/11472
LA en
DS RISalud
RD Apr 6, 2025