Department of Medical Genetics, Cambridge Institute for Medical Research, University of Cambridge, Cambridge, UK.
J Med Genet. 2011 Feb;48(2):131-5. doi: 10.1136/jmg.2010.081455. Epub 2010 Oct 26.
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.
神经生长因子β（NGFβ）和酪氨酸激酶受体 A 型（TRKA）是研究较为深入的神经营养因子/受体对，参与神经元的存活和分化。唯一先前报道的由 NGF 突变引起的遗传性感觉神经病，c.661C>T（HSAN5），以及 TRKA 基因（NTRK1）双等位基因突变引起的病理（HSAN4），仅具有一些共同的临床特征。本文报道了一个阿拉伯近亲家族，其中六个孩子中的五个完全无法感知疼痛，智力迟钝，不排汗，无法区分温度，且存在慢性免疫缺陷。该病症与 NGF 基因中的一个新的纯合突变有关，c.[680C>A]+[681_682delGG]。
使用遗传连锁和标准测序技术来鉴定致病基因。通过将野生型或突变型过表达构建体转染到 PC12 和 COS-7 细胞中，研究了突变的细胞和分子后果。
突变基因产生了一种无法分化 PC12 细胞的前体蛋白 V232fs。V232fs 不能像成熟的 NGFβ一样从细胞中分泌出来。
临床和细胞数据均表明，c.[680C>A]+[681_682delGG]NGF 突变是功能缺失型的。HSAN5 表型扩展至包含 HSAN4 样特征。因此，HSAN4 和 HSAN5 表型是 NGF/TRKA 信号通路改变引起的表型谱的一部分。
