The elusive multiple self-healing squamous epithelioma (MSSE) gene: further mapping, analysis of candidates, and loss of heterozygosity

Abstract

The MSSE gene predisposes to multiple invasive but selfhealing skin tumours (multiple self-healing epitheliomata). MSSE was previously mapped to chromosome 9q22-q31 and a shared haplotype in affected families suggested a founder mutation. We have refined the MSSE critical region (o1 cM, o1 Mb) between the zinc-finger gene ZNF169 and the Fanconi anaemia gene FANCC. By genetic mapping we have excluded ZNF169 and FANCC as well as PTCH (PATCHED) and TGFBR1 (transforming growth factor beta receptor type-1) genes. The CDC14B cell cycle phosphatase gene also lies in the region but screening of the complete coding region revealed no mutation in MSSE patients. Somatic cell hybrids created by haploid conversion of an MSSE patient's cells enabled screening of the MSSE chromosome 9 and showed no CDC14B deletion or mutation that abrogates CDC14B mRNA expression. Thus, CDC14B is unlikely to be the MSSE gene. We also report the first molecular analysis of MSSE tumours showing loss of heterozygosity of the MSSE region, with loss of the normal allele, providing the first evidence that MSSE is a tumour suppressor gene.

Severe exacerbation of multiple self-healing squamous epithelioma (Ferguson–Smith disease) with radiotherapy, which was successfully treated with acitretin

“…The condition was originally thought to be caused by a founder mutation, and linkage analysis of nine MSSE Scottish families identified a 4‐cM candidate region on chromosome 9q22–q31 5 . Loss of heterozygosity around this region was subsequently shown, suggesting that the MSSE gene might be a tumour suppressor gene 6 . The coding regions of the 14 known genes within the MSSE locus, including PTCH , ZNF169 and FANCC , were sequenced, but no mutation was identified 1 .…”

“…5 Loss of heterozygosity around this region was subsequently shown, suggesting that the MSSE gene might be a tumour suppressor gene. 6 The coding regions of the 14 known genes within the MSSE locus, including PTCH, ZNF169 and FANCC, were sequenced, but no mutation was identified. 1 The XPA gene, mutations of which cause xeroderma pigmentosum, had already been excluded by a previous study.…”

Putting Medical Genetics into Practice

“…Two possible candidate genes in the region, xeroderma pigmentosum and PATCHED (mutated in familial basal cell carcinoma), were checked and excluded for mutations by Frances Richards in our group (115). Richards went on to exclude other candidates and to demonstrate loss of heterozygosity within the critical region in tumors, thus providing the first evidence that the MSSE gene was a tumor suppressor gene (7). Families with the condition were now being referred to us from Italy, Japan, Denmark, France, and the United States with linkage to 9q31 but with different haplotypes (19).…”

Multiple Self-Healing Squamous Epithelioma (MSSE): Rare Variants in an Adjacent Region of Chromosome 9q22.3 to Known TGFBR1 Mutations Suggest a Digenic or Multilocus Etiology

“…TGFBR1 mutations in MSSE are functionally null implying a tumor suppressor action in this disease, whereas mis sense mutations in the same gene can lead to Marfan syndrome-related disorders (Goudie et al, 2011; Loeys et al, 2005). TGFBR1 had previously been excluded as a MSSE candidate because the gene lies outside the original shared at-risk haplotype (SRH) in the Scottish families (Bose et al , 2006). However using large scale sequencing technology, Goudie et al (2011) identified TGFBR1 germline mutations in a total of 18 MSSE families including 12 Scottish families.…”