Mutations inSDR9C7gene encoding an enzyme for vitamin A metabolism underlie autosomal recessive congenital ichthyosis

Abstract

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.

Inherited Nonsyndromic Ichthyoses: An Update on Pathophysiology, Diagnosis and Treatment

“…ARCI is caused by mutations in more than a dozen different genes, including TGM1 [ 33 ] , ABCA12 [ 34 ], CYP4F22 [ 35 ], ALOXE3/ALOX12B [ 36 ], NIPAL4 [ 37 ], CERS3 [ 38 – 40 ], SDR9C7 [ 41 ], PNPLA1 [ 42 – 44 ], SLC27A4 [ 45 ], and LIPN [ 46 ], a very rare cause of non-congenital ichthyosis not discussed in this context. Also relevant for a discussion of ARCI pathogenesis is ELOVL4 [ 47 ], a gene which is associated with syndromic ichthyosis, but nonetheless operates with the ARCI genes in a metabolic pathway essential for the production of a specific acylceramide moiety, ω-hydroxy-acylceramide (ω-HAC), eventually bound to the CE (see Fig.…”

“…SDR9C7 This is the most recently identified ARCI gene, encoding a protein belonging to the family of short-chain dehydrogenase/reductases [ 41 , 74 ]. These enzymes are known to catalyze the metabolism of various ligands for nuclear receptors, such as prostaglandins, retinoids, and several classes of steroid hormones.…”

Recent advances in understanding inherited disorders of keratinization

“…In 2016, Shigehara et al . described a homozygous missense mutation in short-chain dehydrogenase/reductase family 9C member 7 (SDR9C7) underlying ARCI in three consanguineous Lebanese families and showed that SDR9C7 is expressed in the granular and cornified layers of the epidermis 22 . The pathomechanism of ichthyosis caused by SDR9C7 deficiency has been debated.…”

Unknown mutations and genotype/phenotype correlations of autosomal recessive congenital ichthyosis in patients from Saudi Arabia and Pakistan

“…Other ARCI genes include cytochrome P450 member CYP4F22, which encodes a fatty acid hydroxylase (Ohno et al, 2015), and defects of this gene have been linked to LI (Lefevre et al, 2006). Mutations in CERS3, PNPLA1, SDR9C7, and SULT2B1, have been identified in few families with ARCI presenting mainly LI phenotypes (Eckl et al, 2013;Grall et al, 2012;Heinz et al, 2017;Israeli et al, 2011;Shigehara et al, 2016).…”