Title |
A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy
|
---|---|
Published in |
Journal of Medical Genetics, October 2010
|
DOI | 10.1136/jmg.2010.081455 |
Pubmed ID | |
Authors |
Ofélia P Carvalho, Gemma K Thornton, Joseph Hertecant, Henry Houlden, Adeline K Nicholas, James J Cox, Mary Rielly, Lihadh Al-Gazali, C Geoffrey Woods |
Abstract |
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>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>A]+[681_682delGG]. 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. The mutant gene produced a precursor protein V232fs that was unable to differentiate PC12 cells. V232fs was not secreted from cells as mature NGFβ. Both the clinical and cellular data suggest that the c.[680C>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. |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United Kingdom | 1 | 2% |
Switzerland | 1 | 2% |
Brazil | 1 | 2% |
Unknown | 62 | 95% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Student > Ph. D. Student | 16 | 25% |
Researcher | 10 | 15% |
Student > Master | 10 | 15% |
Student > Bachelor | 8 | 12% |
Student > Postgraduate | 6 | 9% |
Other | 9 | 14% |
Unknown | 6 | 9% |
Readers by discipline | Count | As % |
---|---|---|
Agricultural and Biological Sciences | 15 | 23% |
Medicine and Dentistry | 11 | 17% |
Biochemistry, Genetics and Molecular Biology | 10 | 15% |
Neuroscience | 10 | 15% |
Psychology | 2 | 3% |
Other | 9 | 14% |
Unknown | 8 | 12% |