Mutations in SDR9C7 gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis

• Published in: Human molecular genetics 2016-10, Vol.25 (20), p.4484-4493
• Main Authors: Shigehara, Yohya, Okuda, Shujiro, Nemer, Georges, Chedraoui, Adele, Hayashi, Ryota, Bitar, Fadi, Nakai, Hiroyuki, Abbas, Ossama, Daou, Laetitia, Abe, Riichiro, Sleiman, Maria Bou, Kibbi, Abdul Ghani, Kurban, Mazen, Shimomura, Yutaka
• Format: Article
• Language: English
• Subjects: Adolescent; Child; DNA Mutational Analysis; Female; Gene Expression; Humans; Ichthyosis - enzymology; Ichthyosis - genetics; Lebanon; Male; Mutation, Missense; Oxidoreductases - genetics; Oxidoreductases - metabolism; Pedigree; Skin - enzymology; Vitamin A - metabolism; Young Adult
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddw277

Autosomal recessive congenital ichthyosis (ARCI) is a heterogeneous group of hereditary skin disorder characterized by an aberrant cornification of the epidermis. ARCI is classified into a total of 11 subtypes (ARCI1-ARCI11) based on their causative genes or loci. Of these, the causative gene for only ARCI7 has not been identified, while it was previously mapped on chromosome 12p11.2-q13.1. In this study, we performed genetic analyses for three Lebanese families with ARCI, and successfully determined the linkage interval to 9.47 Mb region on chromosome 12q13.13-q14.1, which was unexpectedly outside of the ARCI7 locus. Whole-exome sequencing and the subsequent Sanger sequencing led to the identification of missense mutations in short chain dehydrogenase/reductase family 9C, member 7 (SDR9C7) gene on chromosome 12q13.3, i.e. two families shared an identical homozygous mutation c.599T > C (p.Ile200Thr) and one family had another homozygous mutation c.214C > T (p.Arg72Trp). In cultured cells, expression of both the mutant SDR9C7 proteins was markedly reduced as compared to wild-type protein, suggesting that the mutations severely affected a stability of the protein. In normal human skin, the SDR9C7 was abundantly expressed in granular and cornified layers of the epidermis. By contrast, in a patient’s skin, its expression in the cornified layer was significantly decreased. It has previously been reported that SDR9C7 is an enzyme to convert retinal into retinol. Therefore, our study not only adds a new gene responsible for ARCI, but also further suggests a potential role of vitamin A metabolism in terminal differentiation of the epidermis in humans.