Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum

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.German Research FoundationUniv Hosp Magdeburg, Inst Human Genet, D-39120 Magdeburg, GermanyUniv Hosp Erlangen, Inst Human Genet, Erlangen, GermanyHosp Nacl Ninos Dr Carlos Saenz Herrera, Dept Med, San Jose, Costa RicaKlinikum Bremen Mitte, Bremen, GermanyCHU Vaudois, Dept Med Genet, CH-1011 Lausanne, SwitzerlandUniv Hosp, Dept Pediat Surg, Poitiers, FranceHosp La Fe, Dept Pediat, E-46009 Valencia, SpainAMC Univ Hosp, Dept Pediat Genet, Amsterdam, NetherlandsVanderbilt Univ, Monroe Carell Jr Childrens Hosp, Div Pediat Gastroenterol Hepatol & Nutr, Nashville, TN 37235 USACleveland Clin, Genom Med Inst, Cleveland, OH 44106 USAGuys Hosp, London SE1 9RT, EnglandKariminejad Najmabadi Pathol & Genet Ctr, Tehran, IranGreenwood Genet Ctr, Greenwood, SC 29646 USAUmea Univ, Dept Med Biosci Med & Clin Genet, Umea, SwedenWomens & Childrens Hosp, SA Clin Genet Serv, Adelaide, SA, AustraliaStiftung Deutsch Klin Diagnost GmbH, Fachbereich Kinder & Jugendmed, Wiesbaden, GermanyUniv São Paulo, Dept Pediat, São Paulo, BrazilUniv British Columbia, Dept Pediat, Div Biochem Dis, BC Childrens Hosp, Vancouver, BC V6T 1W5, CanadaCtr Human Genet, Ingelheim, GermanyNanjing Med Univ, Nanjing Childrens Hosp, Dept Digest Dis, Nanjing, Jiangsu, Peoples R ChinaUniv Klinikum Bonn, Zentrum Kinderheilkunde, Bonn, GermanyUniv Tehran Med Sci, Childrens Med Ctr, Res Ctr Immunodeficiencies, Tehran, IranUniv Tehran Med Sci, Dept Immunol, Tehran, IranKing Faisal Specialist Hosp & Res Ctr, Dept Genet, Riyadh 11211, Saudi ArabiaOndokuz Mayis Univ, Dept Med, Samsun, TurkeyOndokuz Mayis Univ, Dept Pediat Genet, Samsun, TurkeyAl Thawra Teaching Hosp, Dept Pediat, Sanaa, YemenHosp Gen Mexico City, Fac Med, Dept Human Genet, Mexico City, DF, MexicoUniv Med Ctr Utrecht, Dept Med Genet, Utrecht, NetherlandsNatl Childrens Hosp, San Jose, Costa RicaSisli Etfal Res Hosp, Dept Med Genet, Istanbul, TurkeyNizams Inst Med Sci, Dept Med Genet, Hyderabad, Andhra Pradesh, IndiaMaulana Azad Med Coll, Dept Pediat, New Delhi, IndiaDeenanath Mangeshkar Hosp & Res Ctr, Dept Genet, Erandawane, IndiaMinist Hlth, Dept Pediat, Manama, BahrainUniv Fed Bahia, Fac Med, Hosp Univ Prof Edgar Santos, Pediat Endocrinol Unit, Salvador, BA, BrazilErnst Moritz Arndt Univ Greifswald, Univ Med, Dept Med A, Greifswald, GermanyTech Univ Munich, Else Kroner Fresenius Zentrum Ernahrungsmed, Freising Weihenstephan, GermanyTech Univ Munich, Zent Inst Ernahrungs & Lebensmittelforsch, Freising Weihenstephan, GermanyTech Univ Munich, Klinikum Rechts Isar, Dept Pediat, D-80290 Munich, GermanyGerman Research Foundation: DFG ZE 524/2-3Web of Scienc