Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.

摘要: Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and typically presenting neonatal period, although milder late-onset (LO) presentation has been reported. More than 90% cases are caused polyalanine repeat mutations (PARMs) C-terminus protein; however non-polyalanine (NPARMs) have Most NPARMs located exon 3 result more severe clinical including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant 1 patient with LO-CCHS no HSCR or PNTs leads translational reinitiation at downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals PHOX2B. In vitro analyses were used determine if these other produced proteins. We found that all tested protein same size. This localized nucleus transactivated target promoter. These data suggest first likely escape mediated decay (NMD) produce proteins functionally distinct from those common PARMs.