TY - JOUR T1 - A novel <em>NGF</em> mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy JF - Journal of Medical Genetics JO - J Med Genet SP - 131 LP - 135 DO - 10.1136/jmg.2010.081455 VL - 48 IS - 2 AU - Ofélia P Carvalho AU - Gemma K Thornton AU - Joseph Hertecant AU - Henry Houlden AU - Adeline K Nicholas AU - James J Cox AU - Mary Rielly AU - Lihadh Al-Gazali AU - C Geoffrey Woods Y1 - 2011/02/01 UR - http://jmg.bmj.com/content/48/2/131.abstract N2 - Background Nerve growth factor β (NGFβ) and tyrosine kinase receptor type A (TRKA) are a well studied neurotrophin/receptor duo involved in neuronal survival and differentiation. The only previously reported hereditary sensory neuropathy caused by an NGF mutation, c.661C&gt;T (HSAN5), and the pathology caused by biallelic mutations in the TRKA gene (NTRK1) (HSAN4), share only some clinical features. A consanguineous Arab family, where five of the six children were completely unable to perceive pain, were mentally retarded, did not sweat, could not discriminate temperature, and had a chronic immunodeficiency, is reported here. The condition is linked to a new homozygous mutation in the NGF gene, c.[680C&gt;A]+[681_682delGG].Methods Genetic linkage and standard sequencing techniques were used to identify the causative gene. Using wild-type or mutant over-expression constructs transfected into PC12 and COS-7 cells, the cellular and molecular consequences of the mutations were investigated.Results The mutant gene produced a precursor protein V232fs that was unable to differentiate PC12 cells. V232fs was not secreted from cells as mature NGFβ.Conclusions Both the clinical and cellular data suggest that the c.[680C&gt;A]+[681_682delGG] NGF mutation is a functional null. The HSAN5 phenotype is extended to encompass HSAN4-like characteristics. It is concluded that the HSAN4 and HSAN5 phenotypes are parts of a phenotypic spectrum caused by changes in the NGF/TRKA signalling pathway. ER -