Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome
Polyalanine expansion and frameshift mutations of the paired-like homeobox gene PHOX2B in congenital central hypoventilation syndrome
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DOI：
10.1038/ng1130
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发表时间：
2003-04-01
期刊：
影响因子：
30.8
通讯作者：
Lyonnet, S
中科院分区：
文献类型：
--
作者：
Amiel, J;Laudier, B;Lyonnet, S
先天性中枢低通气综合征(CCHS或Ondine‘s Curse；OMIM 209880)是一种危及生命的疾病，涉及对高碳酸血症和低氧血症的呼吸反应受损。这种核心表型与自主神经系统(ANS)的低外显率异常有关，包括先天性巨结肠以及神经节神经瘤和神经母细胞瘤等神经脊衍生物的肿瘤。在小鼠中，ANS反射电路的发展依赖于成对的类同源盒基因PHOX2B。因此，我们将其人类同源基因PHOX2B作为CCHS的候选基因。我们在29例CCHS患者中有18例发现了PHOX2B基因的杂合子新突变。大多数突变包括20个残基聚丙氨酸链中5-9个丙氨酸的扩张，可能是由非同源重组引起的。我们发现，在人类胚胎发育过程中，PHOX2B在中枢和外周ANS中都有表达。我们的数据支持PHOX2B在自主呼吸系统的正常模式中的重要作用，更广泛地说，在人类的ANS中。
Congenital central hypoventilation syndrome (CCHS or Ondine's curse; OMIM 209880) is a life-threatening disorder involving an impaired ventilatory response to hypercarbia and hypoxemia. This core phenotype is associated with lower-penetrance anomalies of the autonomic nervous system (ANS) including Hirschsprung disease and tumors of neural-crest derivatives such as ganglioneuromas and neuroblastomas. In mice, the development of ANS reflex circuits is dependent on the paired-like homeobox gene Phox2b. Thus, we regarded its human ortholog, PHOX2B, as a candidate gene in CCHS. We found heterozygous de novo mutations in PHOX2B in 18 of 29 individuals with CCHS. Most mutations consisted of 5-9 alanine expansions within a 20-residue polyalanine tract probably resulting from non-homologous recombination. We show that PHOX2B is expressed in both the central and the peripheral ANS during human embryonic development. Our data support an essential role of PHOX2B in the normal patterning of the autonomous ventilation system and, more generally, of the ANS in humans.