A novel deletion mutation in the DSG4 gene underlies autosomal recessive hypotrichosis with variable phenotype in two unrelated consanguineous families.

BACKGROUND: Autosomal recessive hypotrichosis is a rare human hereditary disorder presenting as sparse scalp hair or as woolly hair occurring on various parts of the body. Various forms of isolated hypotrichosis have been reported to date. Mutations in at least 11 genes have been reported to cause hypotrichosis. AIMS: To investigate the clinical and genetic basis of autosomal recessive hypotrichosis in two unrelated consanguineous families. METHODS: Genotyping by highly polymorphic microsatellite markers established linkage in both families to the DSG4 gene on chromosome 18q21. PCR amplification of exons and intron-exon borders of the DSG4 gene was performed, and the products sequenced to search for disease-causing sequence variants. RESULTS: Clinical investigation revealed typical hypotrichosis in the affected members of one family, while other affected members showed presence of monilethrix-like scalp hair. Sequence analysis of DSG4 revealed a novel deletion mutation (c.85-1_191del) in the affected subjects of both families. CONCLUSIONS: This study further extends the body of evidence that mutations in the DSG4 gene result in both hypotrichosis and monilethrix-like scalp hair.

A novel missense mutation in the gene FZD6 underlies autosomal recessive nail dysplasia.

BACKGROUND: Inherited isolated nail anomaly manifesting with onychauxis and onycholysis is a rare condition, caused by mutations in the gene FZD6, encoding membrane-bound Wnt receptor protein. OBJECTIVES: To search for sequence variants in the gene FZD6 in three individuals of a consanguineous family exhibiting features of nail dysplasia. METHODS: Linkage in the family was searched by genotyping microsatellite markers linked to the gene FZD6, mapped at chromosome 8q22.3. Exons and splice junction sites of the gene FZD6 were polymerase chain reaction amplified and sequenced in an automated DNA sequencer. RESULTS: DNA sequence analysis revealed a novel homozygous missense mutation (c.1266G>A; p.Gly422Asp) located in the transmembrane domain of the protein FZD6. CONCLUSIONS: The missense mutation (p.Gly422Asp), identified here, is only the third mutation detected in the gene FZD6.

Mutations in the P2RY5 gene underlie autosomal recessive hypotrichosis in 13 Pakistani families.

BACKGROUND: Autosomal recessive hypotrichosis is a rare genetic irreversible hair loss characterized by sparse scalp hair, sparse to absent eyebrows and eyelashes, and sparse axillary and body hair. Affected male individuals have normal beard hair. OBJECTIVES: To search for pathogenic mutations in the human P2RY5 gene in Pakistani families with autosomal recessive hereditary hypotrichosis. METHODS: In the present report, 16 unrelated consanguineous Pakistani families having multiple affected individuals with autosomal recessive hypotrichosis were investigated. Linkage in these families was searched by genotyping microsatellite markers linked to autosomal recessive hypotrichosis loci LAH1, LAH2 and LAH3. Thirteen of the families showed linkage to the LAH3 locus on chromosome 13q14.11-q21.32. These families were then subjected to direct sequencing of the P2RY5 gene, which encodes a G protein-coupled receptor. RESULTS: Sequence analysis of the P2RY5 gene revealed two novel missense mutations (c.742A>T; p.N248Y and c.830C>T; p.L277P) in three families. Five previously described mutations including three missense (c.188A>T; p.D63V, c.436G>A; p.G146R, c.562A>T; p.I188F), one insertion (c.69insCATG; p.24insHfsX52) and one complex deletion (c.172-175delAACT; 177delG; p.N58-L59delinsCfsX88) were detected in the other 10 families. CONCLUSIONS: Mutations revealed in the present study extend the body of evidence implicating the P2RY5 gene in the pathogenesis of human hereditary hair loss.