Mutations in the human UBR1 gene and the associated phenotypic spectrum

Maja Sukalo, Ariane Fiedler, Celina Guzmán, Stephanie Spranger, Marie-Claude Addor, Jiad N. Mcheik, Manuel Oltra Benavent, Jan M. Cobben, Lynette A. Gillis, Amy G. Shealy, Charu Deshpande, Bita Bozorgmehr, David B. Everman, Eva-Lena Stattin, Jan Liebelt, Klaus-Michael Keller, Débora Romeo Bertola, Clara D. M. van Karnebeek, Carsten Bergmann, Zhifeng LiuGesche Düker, Nima Rezaei, Fowzan S. Alkuraya, Gönül Oğur, Abdullah Alrajoudi, Carlos A. Venegas-Vega, Nienke E. Verbeek, Erick J. Richmond, Ozgür Kirbiyik, Prajnya Ranganath, Ankur Singh, Koumudi Godbole, Fouad A. M. Ali, Crésio Alves, Julia Mayerle, Markus M. Lerch, Heiko Witt, Martin Zenker

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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 E3 ubiquitin ligase UBR1, which is part of the proteolytic N-end rule pathway. Herein, we review previously reported (n = 29) and a total of 31 novel UBR1 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 UBR1 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 UBR1 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 UBR1 mutations together with their clinical data, a mutation database has been established at LOVD
Original languageEnglish
Pages (from-to)521-531
JournalHuman mutation
Issue number5
Publication statusPublished - 2014

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