A novel NGF mutation clarifies the molecular mechanism and extends the phenotypic spectrum of the HSAN5 neuropathy.
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.
Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
Ofélia P
OP
Carvalho
Gemma K
GK
Thornton
Joseph
J
Hertecant
Henry
H
Houlden
Adeline K
AK
Nicholas
James J
JJ
Cox
Mary
M
Rielly
Lihadh
L
Al-Gazali
C Geoffrey
CG
Woods
D000818:Animals; D001483:Base Sequence; D015153:Blotting, Western; D019556:COS Cells; D002522:Chlorocebus aethiops; D002874:Chromosome Mapping; D004797:Enzyme-Linked Immunosorbent Assay; D005838:Genotype; D009477:Hereditary Sensory and Autonomic Neuropathies / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D020932:Nerve Growth Factor / Q000235:genetics*; D016716:PC12 Cells; D010375:Pedigree; D051381:Rats; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics; D020917:Receptor, trkA / Q000235:genetics; D017422:Sequence Analysis, DNA
D020932:Nerve Growth Factor; D020794:Receptor Protein-Tyrosine Kinases; D020917:Receptor, trkA