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

在先天性中枢性低通气综合征(CCHS)中，大多数患者携带PHOX2B基因的新聚丙氨酸扩张性突变。我们以前报道过从头开始的聚丙氨酸扩增突变起源于父系，起源于精子发生过程中姐妹染色单体的不平等交换。在本研究中，我们分析了PHOX2B单倍型与从头扩增多聚丙氨酸的关系，并证实了从头扩增突变的起源和扩增机制。我们还发现，携带rs17884724：A和GT；C的单倍型在7-丙氨酸扩展(27个丙氨酸)突变等位基因中被频繁检测到，这是CCHS中最常见的突变。含有rs17884724：A&gt；C的等位基因与不含rs17884724：A&gt；C的等位基因相比，在交叉时的核苷酸错配较少。在七个丙氨酸扩展突变中，rs17884724：A&gt；C的高频率也支持多丙氨酸扩展的不等交换机制。然而，超过90%的丙氨酸扩展突变被认为是去新突变，然而，最近的一份报告指出，25%的患者从具有体细胞嵌合体或结构性突变的父母那里遗传了丙氨酸扩展的等位基因。我们研究了45个无关家系的遗传，发现10名患者(22%)从晚发性中枢性低通气综合征的父母或患有体细胞嵌合症的无症状父母那里遗传了丙氨酸扩张突变。为了明确诊断和有效的遗传咨询，需要进行遗传分析。

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.