Missense mutation in exon 7 of TRPS1 gene in an Italian family with a mild form of trichorhinophalangeal syndrome type I

Background Trichorhinophalangeal syndrome (TRPS) is a rare autosomal dominant disorder, three types of which have been described in the literature. All of them are characterized by alopecia, facial dysmorphism and bone deformities. Deletions and nonsense mutations of the TRPS1 gene are responsible for most of the TRPS I and III cases with no clear genotype-phenotype correlation. The majority of missense mutations have been described at TRPS1 exon 6, encoding a presumptive GATA DNA-binding domain, and are known to be associated with the most severe forms of the phenotypic spectrum of TRPS. Mutation mapping at exon 7 described to date includes nonsense mutations and a familial case with an insertion mutation. Objectives To determine a possible correlation between a mutation at exon 7 and mild TRPS phenotype. Methods We describe three members of an Italian family with TRPS I. All three showed clinical features typical of TRPS I such as temporal alopecia and facial abnormalities, but no mental retardation. Results Mutation analysis showed a missense mutation (R952C) in exon 7 of the TRPS1 gene. Conclusions R952C is the first missense mutation described outside the GATA zinc-finger domain of TRPS1. In contrast with missense mutations occurring within this region, this mutation prevents the transport of the TRPS1 protein into the nucleus, therefore determining TRPS I by haploinsufficiency. We hypothesize that a TRPS exon 7 mutation could result in a mild phenotype.