A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy.

Abstract

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>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].

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>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.

• 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
• Journal: Journal of medical genetics (J Med Genet) Vol. 48 Issue 2 Pg. 131-5 (Feb 2011) ISSN: 1468-6244 [Electronic] England
• PMID: 20978020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Nerve Growth Factor
• Receptor Protein-Tyrosine Kinases
• Receptor, trkA

Topics

• Animals
• Base Sequence
• Blotting, Western
• COS Cells
• Chlorocebus aethiops
• Chromosome Mapping
• Enzyme-Linked Immunosorbent Assay
• Genotype
• Hereditary Sensory and Autonomic Neuropathies (genetics, pathology)
• Humans
• Molecular Sequence Data
• Mutation (genetics)
• Nerve Growth Factor (genetics)
• PC12 Cells
• Pedigree
• Rats
• Receptor Protein-Tyrosine Kinases (genetics)
• Receptor, trkA (genetics)
• Sequence Analysis, DNA