Inflammatory peeling skin syndrome caused by homozygous genomic deletion in the PSORS1 region encompassing the CDSN gene

Abstract

Peeling skin syndrome (PSS) type B is a rare recessive genodermatosis characterized by lifelong widespread, reddish peeling of the skin with pruritus. The disease is caused by smallscale mutations in the Corneodesmosin gene (CDSN) leading to premature termination codons. We report for the first time a Japanese case resulting from complete deletion of CDSN. Corneodesmosin was undetectable in the epidermis, and CDSN was unamplifiable by PCR. QMPSF analysis demonstrated deletion of CDSN exons inherited from each parent. Deletion mapping using microsatellite haplotyping, CGH array and PCR analysis established that the genomic deletion spanned 49-72 kb between HCG22 and TCF19, removing CDSN as well as five other genes within the psoriasis susceptibility region 1 (PSORS1) on 6p21.33. This observation widens the spectrum of molecular defects underlying PSS type B and shows that loss of these five genes from the PSORS1 region does not result in an additional cutaneous phenotype.

A comprehensive next‐generation sequencing assay for the diagnosis of epidermolysis bullosa

“…Clinically, there are four main types of EB: EB simplex (EBS), caused by mutations in 14 different genes; junctional EB (JEB), now known to be caused by mutations in eight different genes; dystrophic EB (DEB), caused by mutations in collagen 7A1 (COL7A1); and Kindler syndrome, caused by mutations in FERMT1 (Table ). We included two genes listed for convenience under the EBS subtype, carbohydrate sulfotransferase 8 (CHST8) and corneodesmosin (CDSN), because they have been reported in fragile skin syndromes. The 2014 EB classification lists only 11 genes for EBS .…”

“…We found five cases3,17,22,29,31 in which there were additional VUCS in the same causative gene. There were five cases5,10,15,23,30 in which there were two homozygous or compound heterozygous VUCS in fragile skin genes other than the causative gene. There were also…”

Genetic skin diseases related to desmosomes and corneodesmosomes

“…Type B may also be associated with several noncutaneous anomalies and various abnormal laboratory findings. In type B PSD, ultrastructural features of corneodesmosomes and skin separation recapitulated those in the CDSN knock-out mice [30]. Dominant nonsense mutations in CDSN that produce a truncated form of CDSN underlie hypotrichosis simplex of the scalp, a rare disease that leads to complete baldness in young adults [32].…”

“…Next in human studies, type B peeling skin disease (PSD) was found to be caused by the absence of functional corneodesmosin expression (Table 1, Fig. 2) [29,30]. PSD is a rare autosomal recessive genodermatosis characterized by continuous superficial exfoliation of the outer epidermis.…”

Phylogenetic profiling and gene expression studies implicate a primary role of PSORS1C2 in terminal differentiation of keratinocytes

“…Thus, the loss of functional PSORS1C2 in cetaceans is in line with the loss of this programme. In humans, homozygous deletions of six different genes including CDSN and PSORS1C2 are associated with generalized peeling skin disease . As the inactivation of CDSN alone is sufficient to induce peeling skin disease, these clinical cases are not informative about the role of PSORS1C2 , as the latter may be obscured by the effects of lack of CDSN .…”