A Novel c.676_677insG PHOX2B Mutation in Congenital Central Hypoventilation Syndrome.

ABSTRACT: Paired-like homeobox (PHOX)2B is considered to be the causative gene of congenital central hypoventilation syndrome (CCHS), a dominant genetic disorder that results in abnormal central respiratory control with resulting hypoventilation during sleep. In this study, we report a novel c.676_677insG (p.Ala226fs) mutation in a patient with severe CCHS, and we evaluated the function of this mutation. The mutation reduced the translation of the mutant PHOX2B protein and impaired its ability to activate the PHOX2A promoter, due to a haploinsufficiency effect. The mutant PHOX2B was able to interact with wildtype PHOX2B, resulting in retention of PHOX2B on the nuclear membrane, which may impair the normal function of the nuclear membrane, and leading to cellular morbidity. Our study provides useful information for the functional studies of PHOX2B and understanding the pathogenesis of CCHS, and thus is beneficial for the prognosis of, genetic counseling for, and development of pharmaceuticals for PHOX2B-associated diseases.