title: Nonsense pathogenic variants in exon 1 of PHOX2B lead to translational reinitiation in congenital central hypoventilation syndrome.
abstract: Pathogenic variants in PHOX2B lead to congenital central hypoventilation syndrome (CCHS), a rare disorder of the nervous system characterized by autonomic dysregulation and hypoventilation typically presenting in the neonatal period, although a milder late-onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C-terminus of the protein; however non-polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of PHOX2B and result in a more severe clinical presentation including Hirschsprung disease (HSCR) and/or peripheral neuroblastic tumors (PNTs). A previously reported nonsense pathogenic variant in exon 1 of a patient with LO-CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N-terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of PHOX2B. In vitro analyses were used to determine if these and other reported nonsense variants in PHOX2B exon 1 produced N-terminally truncated proteins. We found that all tested nonsense variants in PHOX2B exon 1 produced a truncated protein of the same size. This truncated protein localized to the nucleus and transactivated a target promoter. These data suggest that nonsense pathogenic variants in the first exon of PHOX2B likely escape nonsense mediated decay (NMD) and produce N-terminally truncated proteins functionally distinct from those produced by the more common PARMs.
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Jacob T
authors.initials: JT
authors.lastname: Cain
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Dae I
authors.initials: DI
authors.lastname: Kim
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Megan
authors.initials: M
authors.lastname: Quast
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Winnie G
authors.initials: WG
authors.lastname: Shivega
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.
authors.forename: Ryan J
authors.initials: RJ
authors.lastname: Patrick
authors.affiliation: Section of Pediatric Pulmonology, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Chuanpit
authors.initials: C
authors.lastname: Moser
authors.affiliation: Section of Neonatal-Perinatal Medicine, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Reuter
authors.affiliation: Department of Pediatric Pulmonology, Kaiser Permanente, Roseville, California.
authors.forename: Myrza
authors.initials: M
authors.lastname: Perez
authors.affiliation: Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Angela
authors.initials: A
authors.lastname: Myers
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.|Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Weimer
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.|Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Roux
authors.affiliation: Children's Health Research Center, Sanford Research, Sioux Falls, South Dakota.|Department of Pediatrics, Sanford School of Medicine at the University of South Dakota, Sioux Falls, South Dakota.
authors.forename: Megan
authors.identifier: http://orcid.org/0000-0002-3423-3895
authors.initials: M
authors.lastname: Landsverk
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics; D005091:Exons / Q000235:genetics; D006627:Hirschsprung Disease / Q000235:genetics* / Q000473:pathology; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007040:Hypoventilation / Q000151:congenital* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D010455:Peptides / Q000235:genetics; D011401:Promoter Regions, Genetic; D014176:Protein Biosynthesis; D020449:Repetitive Sequences, Amino Acid / Q000235:genetics; D020182:Sleep Apnea, Central / Q000235:genetics* / Q000473:pathology; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; D018398:Homeodomain Proteins; C109220:NBPhox protein; D010455:Peptides; D014157:Transcription Factors; C019529:polyalanine
keywords: CCHS; PHOX2B; mRNA reinitiation