Multiple cutaneous and uterine leiomyomata resulting from missense mutations in the fumarate hydratase gene.

Multiple cutaneous and uterine leiomyomata (MCL) is an autosomal dominant disorder characterized by the development of benign smooth muscle tumours (leiomyomas) in the skin and uterus of affected women, and in the skin of affected men. In rare cases, MCL has been associated with a predisposition to the rare type II papillary renal cell cancer, also known as hereditary leiomyomatosis and renal cell cancer. The genetic locus for MCL has been mapped to chromosome 1q42.3-43 and subsequently, germline mutations in the fumarate hydratase (FH) gene have been identified. In addition, analysis of FH in some tumours of MCL patients revealed a second mutation inactivating the wild-type allele, suggesting that FH may function as a tumour suppressor gene. Here, we report two cases of MCL patients with FH mutations, designated as T287P and R190L. T287P represents a novel mutation of a highly conserved amino acid of the FH protein. In addition, a patient with an unusual clinical presentation of MCL was found to have the recurrent mutation, R190L, raising the possibility of incorporating FH sequencing as a diagnostic tool. Our findings extend the allelic series of mutations in FH and support its status as the underlying cause of MCL.

A novel missense mutation in the COL7A1 gene underlies epidermolysis bullosa pruriginosa.

Epidermolysis bullosa (EB) pruriginosa is a subtype of dominant dystrophic EB (DDEB), characterized by severe pruritus and blistering localized to the extensor surface of the extremities. EB pruriginosa exhibits extensive clinical heterogeneity with variable expression and delayed age of onset. Mutations in the COL7A1 gene, especially in glycine residues within Gly-X-Y repeats, have been shown to cause this form of DDEB. Here, we report a novel COL7A1 mutation in a Taiwanese pedigree with EB pruriginosa. Using PCR and direct sequence analysis we have identified a G-->T transversion at nucleotide 7097 in exon 92 of COL7A1, converting a glycine residue to valine (G2366V). The mutation resides within a consecutive, uninterrupted stretch of 17 Gly-X-Y residues in the triple-helical domain of type VII collagen. Interestingly, an affected member of this family also displayed elevated IgE levels, previously reported in some patients with this disorder. Our finding further implicates COL7A1 mutation in the pathogenesis of EB pruriginosa and underscores the heterogeneous clinical symptoms of glycine mutations in DDEB.

Atrichia with papular lesions resulting from a novel homozygous missense mutation in the hairless gene.

Atrichia with papular lesions (APL) is a rare autosomal recessive disorder resulting in complete and irreversible hair loss shortly after birth. Affected individuals also develop papular lesions of keratin-filled follicular cysts over extensive areas of the body. Mutations in the hairless gene, a putative single zinc-finger transcription factor protein, have been implicated in the pathogenesis of APL. In this report, we describe a novel missense mutation, E583V, in the hairless gene in an Italian family affected with APL. The mutation resides between the LXXLL motif found in TRIPs (thyroid hormone receptor interacting proteins) in exon 5 and the six-cysteine zinc-finger motif in exon 6. The amino acid sequence neighbouring the LXXLL motif and zinc-finger domain is highly conserved in human, monkey, rat, and mouse hairless proteins. Our finding extends the body of evidence that supports the importance of the zinc-finger and LXXLL domains in the function of the hairless protein. Moreover, we continue to find small APL families without consanguinity from around the world.