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Congenital insensitivity to pain with anhidrosis : phenotypes and mutations in TRKA(NTRK1) gane encoding the receptor tyrosine kinase for nerve growth factor

先天性疼痛不敏感伴无汗症：编码神经生长因子受体酪氨酸激酶的 TRKA(NTRK1) gane 的表型和突变

基本信息

批准号：
15590292
负责人：
INDO Yasuhiro
金额：
$ 2.3万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

1.The human TRKA gene(NTRK1), located on chromosome 1q21-q22 encodes the receptor tyrosine kinase for nerve growth factor. We reported that TRKA is the gene responsible for congenital insensitivity to pain with anhidrosis(CIPA). We here further report eight novel mutations detected as either a homozygous or heterozygous state in nine CIPA families from five countries.2.Mendelian inheritance of the mutations was confirmed in seven families for which samples from either parent were available. However, non-mendelian inheritance seems for likely for the family when only samples from the mother and siblings, (but not from the farther) were available. A paternal uniparental disomy for chromosome 1 is likely to be the cause of reduction to homozygosity of the TRKA gene mutation in this family.3.A Hispanic patient from the USA has two autosomal genetic disorders, CIPA and pyruvate kinase deficiency, whose genetic loci are both mapped to a closely linked chromosomal region. A splice mutation and a missense mutation were detected in the TRKA and PKLR genes from the homozygous proband, respectively. Thus, concomitant occurrence of two disorders is ascribed to a combination of two separate mutant genes, not a contiguous gene syndrome. This finding suggests a mechanism responsible for two autosomal genetic disorders in one patient.4.We introduced the putative missense mutations into the TRKA cDNA, using in vitro mutagenesis, and examined NGF-stimulated autophosphorylation. Mutants in the extracellular domain were aberrantly processed and showed diminished autophosphorylation in neuronal cells. Mutants in the tyrosine kinase domain were processed as wild-type TRKA but significantly diminished autophosphorylation in cells.5.All these data further support findings that TRKA defects can cause CIPA in various ethnic groups. This will aid in diagnosis and genetic counseling of this painless but severe genetic disorders.

1.人TRKA基因（NTRK 1）位于染色体1 q21-q22上，编码神经生长因子的受体酪氨酸激酶。我们报道了TRKA基因是先天性无痛无汗症（CIPA）的致病基因。本文进一步报道了来自5个国家的9个CIPA家系中发现的8个新的纯合或杂合突变。2.在7个家系中证实了突变的孟德尔遗传，其中7个家系的样本来自父母之一。然而，非孟德尔遗传似乎是可能的家庭时，只有样本的母亲和兄弟姐妹，但不是从较远的）。1号染色体的父系单亲二体性可能是该家系TRKA基因突变降低至纯合性的原因。3.一名来自美国的西班牙裔患者患有两种常染色体遗传病，CIPA和丙酮酸激酶缺乏症，其遗传位点均定位于一个紧密连锁的染色体区域。在纯合子先证者的TRKA和PKLR基因中分别检测到剪接突变和错义突变。因此，两种疾病的同时发生归因于两个单独的突变基因的组合，而不是连续基因综合征。这一发现表明一种机制导致一名患者出现两种常染色体遗传性疾病。4.我们使用体外突变将推定的错义突变引入TRKA cDNA，并检查了NGF刺激的自磷酸化。细胞外结构域中的突变体被异常处理，并在神经元细胞中显示出减少的自磷酸化。酪氨酸激酶结构域的突变体被加工为野生型TRKA，但显著减少细胞中的自磷酸化。所有这些数据进一步支持TRKA缺陷可导致不同种族的CIPA的发现。这将有助于这种无痛但严重的遗传疾病的诊断和遗传咨询。