{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,20]],"date-time":"2026-03-20T03:20:21Z","timestamp":1773976821629,"version":"3.50.1"},"reference-count":40,"publisher":"Wiley","issue":"5","license":[{"start":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T00:00:00Z","timestamp":1490745600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["P20 GM103620"],"award-info":[{"award-number":["P20 GM103620"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000009","name":"Foundation for the National Institutes of Health","doi-asserted-by":"publisher","award":["P20 GM103548"],"award-info":[{"award-number":["P20 GM103548"]}],"id":[{"id":"10.13039\/100000009","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J of Med Genetics Pt A"],"published-print":{"date-parts":[[2017,5]]},"abstract":"<jats:sec><jats:label\/><jats:p>Pathogenic variants in <jats:italic>PHOX2B<\/jats:italic> 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\u2010onset (LO) presentation has been reported. More than 90% of cases are caused by polyalanine repeat mutations (PARMs) in the C\u2010terminus of the protein; however non\u2010polyalanine repeat mutations (NPARMs) have been reported. Most NPARMs are located in exon 3 of <jats:italic>PHOX2B<\/jats:italic> 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\u2010CCHS and no HSCR or PNTs leads to translational reinitiation at a downstream AUG codon producing an N\u2010terminally truncated protein. Here we report additional individuals with nonsense pathogenic variants in exon 1 of <jats:italic>PHOX2B<\/jats:italic>. In vitro analyses were used to determine if these and other reported nonsense variants in <jats:italic>PHOX2B<\/jats:italic> exon 1 produced N\u2010terminally truncated proteins. We found that all tested nonsense variants in <jats:italic>PHOX2B<\/jats:italic> 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 <jats:italic>PHOX2B<\/jats:italic> likely escape nonsense mediated decay (NMD) and produce N\u2010terminally truncated proteins functionally distinct from those produced by the more common PARMs.<\/jats:p><\/jats:sec>","DOI":"10.1002\/ajmg.a.38162","type":"journal-article","created":{"date-parts":[[2017,3,29]],"date-time":"2017-03-29T09:43:34Z","timestamp":1490780614000},"page":"1200-1207","source":"Crossref","is-referenced-by-count":25,"title":["Nonsense pathogenic variants in exon 1 of <i>PHOX2B<\/i> lead to translational reinitiation in congenital central hypoventilation syndrome"],"prefix":"10.1002","volume":"173","author":[{"given":"Jacob T.","family":"Cain","sequence":"first","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Dae I.","family":"Kim","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Megan","family":"Quast","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Winnie G.","family":"Shivega","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ryan J.","family":"Patrick","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chuanpit","family":"Moser","sequence":"additional","affiliation":[{"name":"Section of Pediatric Pulmonology Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Suzanne","family":"Reuter","sequence":"additional","affiliation":[{"name":"Section of Neonatal\u2010Perinatal Medicine Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Myrza","family":"Perez","sequence":"additional","affiliation":[{"name":"Department of Pediatric Pulmonology Kaiser Permanente Roseville California"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Angela","family":"Myers","sequence":"additional","affiliation":[{"name":"Department of Pediatrics Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jill M.","family":"Weimer","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"},{"name":"Department of Pediatrics Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyle J.","family":"Roux","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"},{"name":"Department of Pediatrics Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3423-3895","authenticated-orcid":false,"given":"Megan","family":"Landsverk","sequence":"additional","affiliation":[{"name":"Children's Health Research Center Sanford Research Sioux Falls South Dakota"},{"name":"Department of Pediatrics Sanford School of Medicine at the University of South Dakota Sioux Falls South Dakota"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2017,3,29]]},"reference":[{"key":"e_1_2_9_2_1","doi-asserted-by":"publisher","DOI":"10.1089\/104454900439773"},{"key":"e_1_2_9_3_1","doi-asserted-by":"publisher","DOI":"10.1038\/ng1130"},{"key":"e_1_2_9_4_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200605-607CR"},{"key":"e_1_2_9_5_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi188"},{"key":"e_1_2_9_6_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200602-305OC"},{"issue":"1","key":"e_1_2_9_7_1","first-page":"1","article-title":"Neurocristopathy: Its growth and development in 20 years. Pediatric pathology & laboratory medicine","volume":"17","author":"Bolande R. P.","year":"1997","journal-title":"Journal of the Society for Pediatric Pathology, Affiliated With the International Paediatric Pathology Association"},{"key":"e_1_2_9_8_1","doi-asserted-by":"publisher","DOI":"10.1186\/1752-1947-7-117"},{"key":"e_1_2_9_9_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M508368200"},{"key":"e_1_2_9_10_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.00866"},{"key":"e_1_2_9_11_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.nbd.2012.10.019"},{"key":"e_1_2_9_12_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M115.679027"},{"key":"e_1_2_9_13_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200411-1528OC"},{"key":"e_1_2_9_14_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2009.139"},{"key":"e_1_2_9_15_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.semcdb.2010.07.006"},{"key":"e_1_2_9_16_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20744"},{"key":"e_1_2_9_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20913"},{"key":"e_1_2_9_18_1","doi-asserted-by":"publisher","DOI":"10.1053\/j.semnuclmed.2007.02.009"},{"key":"e_1_2_9_19_1","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M405024200"},{"key":"e_1_2_9_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.21527"},{"key":"e_1_2_9_21_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.10310"},{"key":"e_1_2_9_22_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.23051"},{"key":"e_1_2_9_23_1","doi-asserted-by":"publisher","DOI":"10.1007\/s11325-014-0996-7"},{"key":"e_1_2_9_24_1","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2003.015412"},{"key":"e_1_2_9_25_1","doi-asserted-by":"publisher","DOI":"10.1038\/ejhg.2015.176"},{"key":"e_1_2_9_26_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.2401811"},{"key":"e_1_2_9_27_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.9516"},{"key":"e_1_2_9_28_1","doi-asserted-by":"publisher","DOI":"10.1242\/dev.127.7.1349"},{"key":"e_1_2_9_29_1","doi-asserted-by":"publisher","DOI":"10.1038\/20700"},{"key":"e_1_2_9_30_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccm.2014.06.010"},{"key":"e_1_2_9_31_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.2008.01039.x"},{"key":"e_1_2_9_32_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.23236"},{"key":"e_1_2_9_33_1","doi-asserted-by":"publisher","DOI":"10.1261\/rna.815108"},{"key":"e_1_2_9_34_1","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.20074"},{"key":"e_1_2_9_35_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200707-1079OC"},{"key":"e_1_2_9_36_1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi401"},{"key":"e_1_2_9_37_1","doi-asserted-by":"publisher","DOI":"10.1002\/humu.20923"},{"key":"e_1_2_9_38_1","doi-asserted-by":"publisher","DOI":"10.1016\/j.rmr.2013.03.007"},{"key":"e_1_2_9_39_1","doi-asserted-by":"publisher","DOI":"10.1164\/rccm.200807-1069ST"},{"key":"e_1_2_9_40_1","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.171.1.950"},{"key":"e_1_2_9_41_1","doi-asserted-by":"publisher","DOI":"10.1002\/ajmg.a.20527"}],"container-title":["American Journal of Medical Genetics Part A"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajmg.a.38162","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.38162","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/full-xml\/10.1002\/ajmg.a.38162","content-type":"application\/xml","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajmg.a.38162","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,8,28]],"date-time":"2023-08-28T08:45:50Z","timestamp":1693212350000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajmg.a.38162"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,3,29]]},"references-count":40,"journal-issue":{"issue":"5","published-print":{"date-parts":[[2017,5]]}},"alternative-id":["10.1002\/ajmg.a.38162"],"URL":"https:\/\/doi.org\/10.1002\/ajmg.a.38162","archive":["Portico"],"relation":{},"ISSN":["1552-4825","1552-4833"],"issn-type":[{"value":"1552-4825","type":"print"},{"value":"1552-4833","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,3,29]]}}}