A novel splice-site mutation in the AAGAB gene segregates with hereditary punctate palmoplantar keratoderma and congenital dysplasia of the hip in a large family

Background Palmoplantar keratoderma punctata (PPKP) is a heterogeneous group of disorders characterized by hyperkeratotic papules occurring over the palms and soles during adolescence. PPKP type 1, also known as PPKP Buschke-Fischer-Brauer type, was recently found to result from mutations in the AAGAB gene, encoding the p34 protein. PPKP type 1 is usually not associated with extracutaneous features. Aim To investigate a large family in which PPKP1 was present in association with congenital dysplasia of the hip (CDH). Methods A combination of direct sequencing of candidate genes and reverse-transcription PCR was used to identify the molecular basis underlying the clinical features displayed by the patients. Results Direct sequencing showed a novel intronic mutation in AAGAB, which was found to cosegregate with PPKP and CDH throughout the family. The mutation was found to result in aberrant RNA splicing, leading to exon 4 skipping. Conclusions This observation suggests either the existence of a CDH-associated gene in the vicinity of AAGAB, or a hitherto unrecognized role for p34 during skeletal development.