Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome
Inheritance of polyalanine expansion mutation of PHOX2B in congenital central hypoventilation syndrome
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DOI：
10.1038/jhg.2012.27
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发表时间：
2012-05-01
影响因子：
3.5
通讯作者：
Hayasaka, Kiyoshi
中科院分区：
文献类型：
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作者：
Meguro, Toru;Yoshida, Yuki;Hayasaka, Kiyoshi
先天性中枢性换气不足综合征（CCHS; MIM 209880）主要由PHOX 2B中的显性丙氨酸扩增（最普遍的是7-丙氨酸扩增）突变引起。超过90%的丙氨酸扩增突变被认为是由于配子发生过程中的不平等交换而从头发生的。然而，最近的一份报告指出，25%的患者从其父母那里遗传了丙氨酸扩增等位基因，并伴有体细胞嵌合或组成型突变。我们研究了45个无关家族的遗传，发现1例患者（2%）从患有晚发性中枢性肺换气不足综合征的父母那里遗传了5-丙氨酸扩展突变，9例患者（20%）从具有体细胞嵌合现象的明显无症状的父母那里遗传了5-至7-丙氨酸扩展突变。由于CCHS先证者的体细胞嵌合体发生率高，建议对所有先证者的父母进行敏感的分析。丙氨酸收缩等位基因（预期对应等位基因在不平等的交叉）和6-丙氨酸扩展突变的体细胞嵌合体的最高患病率的情况下，体细胞嵌合体可能是由一种机制，而不是不平等的交叉，如复制机制。Journal of Human Genetics（2012）57，335-337; doi：10.1038/jhg.2012.27; 2012年3月22日在线发表
Congenital central hypoventilation syndrome (CCHS; MIM 209880) is caused mostly by dominant alanine expansion (most prevalent is 7-alanine expansion) mutations in PHOX2B. More than 90% of the alanine expansion mutations had been considered to be de novo due to unequal crossover during gametogenesis. 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 one patient (2%) inherited 5-alanine expansion mutation from a parent with late-onset central hypoventilation syndrome and nine patients (20%) inherited 5- to 7-alanine expansion mutation from apparently asymptomatic parents with somatic mosaicism. Analysis using a sensitive method would be recommended to all parents of CCHS proband due to high incidence of somatic mosaicism. The absence of an alanine-contracted allele (expected counterpart allele in unequal crossover) and the highest prevalence of 6-alanine expansion mutation in somatic mosaicism suggest that the somatic mosaicism is likely caused by a mechanism other than an unequal crossover, such as a replication mechanism. Journal of Human Genetics (2012) 57, 335-337; doi:10.1038/jhg.2012.27; published online 22 March 2012