title: Mutations in the human UBR1 gene and the associated phenotypic spectrum.
abstract: 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.
authors.affiliation: Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.
authors.forename: Maja
authors.initials: M
authors.lastname: Sukalo
authors.forename: Ariane
authors.initials: A
authors.lastname: Fiedler
authors.forename: Celina
authors.initials: C
authors.lastname: Guzmán
authors.forename: Stephanie
authors.initials: S
authors.lastname: Spranger
authors.forename: Marie-Claude
authors.initials: MC
authors.lastname: Addor
authors.forename: Jiad N
authors.initials: JN
authors.lastname: McHeik
authors.forename: Manuel
authors.initials: M
authors.lastname: Oltra Benavent
authors.forename: Jan M
authors.initials: JM
authors.lastname: Cobben
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Gillis
authors.forename: Amy G
authors.initials: AG
authors.lastname: Shealy
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.forename: Bita
authors.initials: B
authors.lastname: Bozorgmehr
authors.forename: David B
authors.initials: DB
authors.lastname: Everman
authors.forename: Eva-Lena
authors.initials: EL
authors.lastname: Stattin
authors.forename: Jan
authors.initials: J
authors.lastname: Liebelt
authors.forename: Klaus-Michael
authors.initials: KM
authors.lastname: Keller
authors.forename: Débora Romeo
authors.initials: DR
authors.lastname: Bertola
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
authors.forename: Carsten
authors.initials: C
authors.lastname: Bergmann
authors.forename: Zhifeng
authors.initials: Z
authors.lastname: Liu
authors.forename: Gesche
authors.initials: G
authors.lastname: Düker
authors.forename: Nima
authors.initials: N
authors.lastname: Rezaei
authors.forename: Fowzan S
authors.initials: FS
authors.lastname: Alkuraya
authors.forename: Gönül
authors.initials: G
authors.lastname: Oğur
authors.forename: Abdullah
authors.initials: A
authors.lastname: Alrajoudi
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Venegas-Vega
authors.forename: Nienke E
authors.initials: NE
authors.lastname: Verbeek
authors.forename: Erick J
authors.initials: EJ
authors.lastname: Richmond
authors.forename: Ozgür
authors.initials: O
authors.lastname: Kirbiyik
authors.forename: Prajnya
authors.initials: P
authors.lastname: Ranganath
authors.forename: Ankur
authors.initials: A
authors.lastname: Singh
authors.forename: Koumudi
authors.initials: K
authors.lastname: Godbole
authors.forename: Fouad A M
authors.initials: FA
authors.lastname: Ali
authors.forename: Crésio
authors.initials: C
authors.lastname: Alves
authors.forename: Julia
authors.initials: J
authors.lastname: Mayerle
authors.forename: Markus M
authors.initials: MM
authors.lastname: Lerch
authors.forename: Heiko
authors.initials: H
authors.lastname: Witt
authors.forename: Martin
authors.initials: M
authors.lastname: Zenker
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics / Q000473:pathology; D001006:Anus, Imperforate / Q000235:genetics* / Q000473:pathology; D030541:Databases, Genetic; D004392:Dwarfism / Q000235:genetics / Q000473:pathology; D004476:Ectodermal Dysplasia / Q000235:genetics* / Q000473:pathology; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006319:Hearing Loss, Sensorineural / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007037:Hypothyroidism / Q000235:genetics* / Q000473:pathology; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D009666:Nose / Q000002:abnormalities* / Q000473:pathology; D010182:Pancreatic Diseases / Q000235:genetics* / Q000473:pathology; D010641:Phenotype; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
chemical_list: C113474:UBR1 protein, human; D044767:Ubiquitin-Protein Ligases
keywords: Johanson-Blizzard syndrome; UBR1; aplasia of alae nasi; cognitive impairment; exocrine pancreatic insufficiency