Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families
Mutation and polymorphism analysis of the TRKA (NTRK1) gene encoding a high-affinity receptor for nerve growth factor in congenital insensitivity to pain with anhidrosis (CIPA) families
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DOI：
10.1007/s004390051018
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发表时间：
2000-01-01
期刊：
影响因子：
5.3
通讯作者：
Indo, Y
中科院分区：
文献类型：
--
作者：
Miura, Y;Mardy, S;Indo, Y
人TRKA基因编码神经生长因子的高亲和力酪氨酸激酶受体。先天性疼痛不敏感伴无汗症（CIPA）是一种常染色体隐性遗传疾病--在许多国家均有报道，其特征为无汗症（不能出汗）、对有害刺激无反应和智力迟钝。我们已经发现TRKA是负责CIPA的基因。我们研究了来自23个无关的日本CIPA家族的46条CIPA染色体中的TRKA。包括此前报道的三起。并鉴定出11个新的突变。四个（L93 P、G516 R、R638 C和D 668 Y）是错义突变，其导致TRK家族（包括TRKA、TRKB和TRKC）中保守位置处的氨基酸取代。三个（S131 fs. L579 fs和D 770 fs）是移码突变。Thr ee（E164 X、Y359 X和R596 X）ale无义突变。另一个是内含子分支位点（IVS 7 - 33 T-->A）突变，在体外引起异常剪接。我们还报告了8个基因内多态性位点的特征，包括一个可变的二核苷酸重复和7个单核苷酸多态性，并描述了在106条正常染色体和46条CIPA染色体中这些位点的等位基因的单倍型关联。超过50%的CIPA染色体共享我们前面描述的移码突变（R548 fs）。这种突变显然与正常染色体中的一种罕见单倍型连锁不平衡，强烈表明它是一种常见的创始者突变。这些发现代表了CIPA突变和相关基因内多态性的第一次广泛分析;它们应该有助于CIPA突变的检测，并有助于这种无痛但严重的遗传性疾病的诊断和遗传咨询。
The human TRKA gene encodes a high-affinity tyrosine kinase receptor for nerve growth factor Congenital insensitivity to pain with anhidrosis (CIPA) is an autosomal recessive genetic disorder-reported from various countries and characterized by anhidrosis (inability to sweat), the absence of reaction to noxious stimuli, and mental retardation. We have found that TRKA is the gene responsible for CIPA. We have studied TRKA in 46 CIPA chromosomes derived from 23 unrelated Japanese CIPA families. including three that have been previously reported. and identified 11 novel mutations. Four (L93P, G516R, R638 C, and D668Y) are missense mutations that result in amino acid substitutions at positions conserved in the TRK family, including TRKA, TRKB, and TRKC. Three (S131 fs. L579 fs, and D770 fs) are frameshift mutations. Thr ee (E164X, Y359X, and R596X) ale nonsense mutations. The other is an intronic branch-site (IVS7-33T-->A) mutation, causing aberrant splicing in vitro. We also report the characterization of eight intragenic polymorphic sites, including a variable dinucleotide repeat and seven single nucleotide polymorphisms, and describe the haplotypic associations of alleles at these sites in 106 normal chromosomes and 46 CIPA chromosomes More than 50% of CIPA chromosomes share the frameshift mutation (R548 fs) that we described earlier. This mutation apparently shows linkage disequilibrium with a rare haplotype in normal chromosomes, strongly suggesting that it is a common founder mutation. These findings represent the first extensive analysis of CIPA mutations and associated intragenic polymorphisms; they should facilitate the detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications.