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Mutations in the Human UBR 1 Gene and the Associated Phenotypic Spectrum
Author(s) -
Sukalo Maja,
Fiedler Ariane,
Guzmán Celina,
Spranger Stephanie,
Addor MarieClaude,
Mcheik Jiad N.,
Oltra Benavent Manuel,
Cobben Jan M.,
Gillis Lynette A.,
Shealy Amy G.,
Deshpande Charu,
Bozorgmehr Bita,
Everman David B.,
Stattin EvaLena,
Liebelt Jan,
Keller KlausMichael,
Bertola Débora Romeo,
Karnebeek Clara D.M.,
Bergmann Carsten,
Liu Zhifeng,
Düker Gesche,
Rezaei Nima,
Alkuraya Fowzan S.,
Oğur Gönül,
Alrajoudi Abdullah,
VenegasVega Carlos A.,
Verbeek Nienke E.,
Richmond Erick J.,
Kirbiyik Özgür,
Ranganath Prajnya,
Singh Ankur,
Godbole Koumudi,
Ali Fouad A. M.,
Alves Crésio,
Mayerle Julia,
Lerch Markus M.,
Witt Heiko,
Zenker Martin
Publication year - 2014
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.22538
Subject(s) - biology , frameshift mutation , genetics , missense mutation , nonsense mutation , phenotype , mutation , gene
Johanson–Blizzard syndrome ( JBS ) is a rare, autosomal recessive disorder characterized by exocrine pancreatic insufficiency, typical facial features, dental anomalies, hypothyroidism, sensorineural hearing loss, scalp defects, urogenital and anorectal anomalies, short stature, and cognitive impairment of variable degree. This syndrome is caused by a defect of the E 3 ubiquitin ligase UBR 1, which is part of the proteolytic N ‐end rule pathway. Herein, we review previously reported ( n = 29) and a total of 31 novel UBR 1 mutations in relation to the associated phenotype in patients from 50 unrelated families. Mutation types include nonsense, frameshift, splice site, missense, and small in‐frame deletions consistent with the hypothesis that loss of UBR 1 protein function is the molecular basis of JBS . There is an association of missense mutations and small in‐frame deletions with milder physical abnormalities and a normal intellectual capacity, thus suggesting that at least some of these may represent hypomorphic UBR 1 alleles. The review of clinical data of a large number of molecularly confirmed JBS cases allows us to define minimal clinical criteria for the diagnosis of JBS . For all previously reported and novel UBR 1 mutations together with their clinical data, a mutation database has been established at LOVD .