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Molecular basis of congenital central hypoventilation syndrome : PHOX2B mutation and its haplotypes

先天性中枢性低通气综合征的分子基础：PHOX2B突变及其单倍型

基本信息

批准号：
21591411
负责人：
SASAKI Ayako
金额：
$ 3万
依托单位：
Yamagata University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2009
资助国家：
日本
起止时间：
2009 至 2011
项目状态：
已结题

项目摘要

With congenital central hypoventilation syndrome (CCHS), most patients carry de novo polyalanine expansion mutation in PHOX2B. We reported previously that de novo polyalanine expansion mutations were of paternal origin and derived from unequal sister chromatid exchange during spermatogenesis. In the present study, we analyzed the relation between the haplotypes and de novo polyalanine expansion in PHOX2B and confirmed the origin and expanded mechanism of de novo polyalanine expansion mutation. We also found that haplotypes carrying rs17884724 : A>C were detected frequently in seven-alanine expanded (27 alanine) mutant alleles, most prevalent mutations in CCHS. The allele with rs17884724 : A>C would make fewer nucleotide mismatches in the misalignment at crossing over than the allele without rs17884724 : A>C. High frequency ofrs17884724 : A>C in seven-alanine expansion mutations would also support the unequal crossover mechanism for polyalanine expansion.More than 90% of the alanine expansion mutations had been considered to be de novo mutation, however, a recent report stated that 25% of patients inherited the alanine-expanded allele from their parents with somatic mosaicism or constitutive mutation. We studied inheritance in 45 unrelated families, and found that 10 patients (22%) inherited alanine expansion mutation from a parent with late-onset central hypoventilation syndrome or asymptomatic parents with somatic mosaicism. Genetic analysis is needed for definite diagnosis and effective genetic counseling.

在先天性中枢性低通气综合征（CCHS）中，大多数患者携带PHOX2B基因的多聚丙氨酸扩展突变。我们以前曾报道过，从头多聚丙氨酸扩增突变的父亲起源，并来自不平等的姐妹染色单体交换精子发生过程中。本研究分析了PHOX 2B基因的单倍型与多聚丙氨酸从头扩增的关系，明确了多聚丙氨酸从头扩增突变的起源和扩增机制。我们还发现携带rs17884724：A>C的单倍型在7个丙氨酸扩展（27个丙氨酸）突变等位基因中频繁检测到，这些突变在CCHS中最普遍。具有rs17884724：A>C的等位基因在交换时的错配中比不具有rs17884724：A>C的等位基因产生更少的核苷酸错配。7个丙氨酸扩展突变中rs17884724：A>C的高频率也支持了多聚丙氨酸扩展的不平等交换机制，超过90%的丙氨酸扩展突变被认为是从头突变，然而，最近的报告指出，25%的患者通过体细胞嵌合或组成型突变从父母那里遗传了丙氨酸扩展等位基因。我们研究了45个无关家族的遗传，发现10例患者（22%）从患有晚发性中枢性肺换气不足综合征的父母或患有体细胞嵌合体的无症状父母那里遗传了丙氨酸扩展突变。基因分析是明确诊断和有效的遗传咨询所必需的。