Fine mapping and identification of a candidate geneSSH1 in disseminated superficial actinic porokeratosis

Abstract

Disseminated superficial actinic porokeratosis (DSAP) is an uncommon autosomal dominant chronic keratinization disorder, characterized by multiple superficial keratotic lesions surrounded by a slightly raised keratotic border. Thus far, although two loci for DSAP have been identified, the genetic basis and pathogenesis of this disorder have not been elucidated yet. In this study, we performed a genome-wide linkage analysis in three Chinese affected families and localized the gene in an 8.0 cM interval defined by D12S330 and D12S354 on chromosome 12. Upon screening 30 candidate genes, we identified a missense mutation, p.Ser63Asn in SSH1 in one family, a frameshift mutation, p.Ser19CysfsX24 in an alternative variant (isoform f) of SSH1 in another family, and a frameshift mutation, p.Pro27ProfsX54 in the same alternative variant in one non-familial case with DSAP. SSH1 encodes a phosphatase that plays a pivotal role in actin dynamics. Our data suggested that cytoskeleton disorganization in epidermal cells is likely associated with the pathogenesis of DSAP.

Lack ofSSH1 mutations in Dutch patients with disseminated superficial actinic porokeratosis: is there really an association?

“…Although it is difficult to understand that we were not able to confirm the results recently published by Zhang et al [2004] in at least one of our own patients, it is still conceivable that our inability to detect any SSH1 mutation could be due to the apparent locus heterogeneity described in DSAP, with at least three different candidate loci reported even within patients of Chinese origin [Xia et al, 2000[Xia et al, , 2002Wei et al, 2003Wei et al, , 2004. Hence, it is possible that mutations in other genes might underlie the disease in our patients of Caucasian background and, perhaps, those of different ethnic origin, too.…”

“…In conclusion, we have reservations as to the association of DSAP with sequence deviations in the SSH1 gene and suggest that other genes within the linkage interval on chromosome 12q should be studied for disease-causing mutations to elucidate the molecular basis of this disorder, in particular since Zhang et al [2004] have not screened all genes located in the critical region between markers D12S330 and D12S1605. ) and exon 13 (SSH1cR13).…”

“…1). Of note, Zhang et al [2004] show no experimental evidence in any of their works for this isoform f of SSH1. This is highly peculiar because if mutations are detected in this isoform, one would like to back this up with experimental evidence and not merely base this assumption on preliminary sequence data in the NCBI database.…”

“…Still, we are surprised that, to date, SSH1 mutations have not even been encountered in other Chinese families with DSAP and linkage to 12q23.2-q24.2. It is also interesting to point out that in their publication from 2004, Zhang et al [2004] show in Figure 1 that the SSH1 gene is located outside of the overlapping consensus linkage region, when considering the three hitherto published linkage reports from Xia et al [2000], Wei et al [2003], and the authors themselves .…”

“…The disease is inherited as an autosomal dominant trait and, to date, linkage in various Chinese families was reportedly established at four different chromosomal loci, 12q23.2-q24.1 [Xia et al, 2000], 12q24.1-q24.2 [Wei et al, 2003], 15q25.1-q26.1 [Xia et al, 2002], and 18p11.3 [Wei et al, 2004], respectively. Following finemapping at chromosome 12q and screening of 30 genes within an 8.0-cM candidate interval between markers D12S330 and D12S354, Zhang et al [2004] reported in 2004 that a missense mutation, S63N, in the slingshot (SSH1) gene (MIM] 606778) and two frameshift mutations, p.Ser19CysfsX24 and p.Pro27ProfsX54, in an alternative splice variant of SSH1, designated isoform f, underlie DSAP in two Chinese families and one patient with a nonfamilial manifestation of the disease .…”