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Mutations in the human UBR1 gene and the associated phenotypic spectrum.
Hum Mutat. 2014 May; 35(5):521-31.HM

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+Show Affiliations

Institute of Human Genetics, University Hospital Magdeburg, Magdeburg, Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

24599544

Citation

Sukalo, Maja, et al. "Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum." Human Mutation, vol. 35, no. 5, 2014, pp. 521-31.
Sukalo M, Fiedler A, Guzmán C, et al. Mutations in the human UBR1 gene and the associated phenotypic spectrum. Hum Mutat. 2014;35(5):521-31.
Sukalo, M., Fiedler, A., Guzmán, C., Spranger, S., Addor, M. C., McHeik, J. N., Oltra Benavent, M., Cobben, J. M., Gillis, L. A., Shealy, A. G., Deshpande, C., Bozorgmehr, B., Everman, D. B., Stattin, E. L., Liebelt, J., Keller, K. M., Bertola, D. R., van Karnebeek, C. D., Bergmann, C., ... Zenker, M. (2014). Mutations in the human UBR1 gene and the associated phenotypic spectrum. Human Mutation, 35(5), 521-31. https://doi.org/10.1002/humu.22538
Sukalo M, et al. Mutations in the Human UBR1 Gene and the Associated Phenotypic Spectrum. Hum Mutat. 2014;35(5):521-31. PubMed PMID: 24599544.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Mutations in the human UBR1 gene and the associated phenotypic spectrum. AU - Sukalo,Maja, AU - Fiedler,Ariane, AU - Guzmán,Celina, AU - Spranger,Stephanie, AU - Addor,Marie-Claude, AU - McHeik,Jiad N, AU - Oltra Benavent,Manuel, AU - Cobben,Jan M, AU - Gillis,Lynette A, AU - Shealy,Amy G, AU - Deshpande,Charu, AU - Bozorgmehr,Bita, AU - Everman,David B, AU - Stattin,Eva-Lena, AU - Liebelt,Jan, AU - Keller,Klaus-Michael, AU - Bertola,Débora Romeo, AU - van Karnebeek,Clara D M, AU - Bergmann,Carsten, AU - Liu,Zhifeng, AU - Düker,Gesche, AU - Rezaei,Nima, AU - Alkuraya,Fowzan S, AU - Oğur,Gönül, AU - Alrajoudi,Abdullah, AU - Venegas-Vega,Carlos A, AU - Verbeek,Nienke E, AU - Richmond,Erick J, AU - Kirbiyik,Ozgür, AU - Ranganath,Prajnya, AU - Singh,Ankur, AU - Godbole,Koumudi, AU - Ali,Fouad A M, AU - Alves,Crésio, AU - Mayerle,Julia, AU - Lerch,Markus M, AU - Witt,Heiko, AU - Zenker,Martin, Y1 - 2014/04/09/ PY - 2013/11/08/received PY - 2014/02/24/accepted PY - 2014/3/7/entrez PY - 2014/3/7/pubmed PY - 2014/12/17/medline KW - Johanson-Blizzard syndrome KW - UBR1 KW - aplasia of alae nasi KW - cognitive impairment KW - exocrine pancreatic insufficiency SP - 521 EP - 31 JF - Human mutation JO - Hum Mutat VL - 35 IS - 5 N2 - 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. SN - 1098-1004 UR - https://www.unboundmedicine.com/medline/citation/24599544/Mutations_in_the_human_UBR1_gene_and_the_associated_phenotypic_spectrum_ DB - PRIME DP - Unbound Medicine ER -