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
PY - 2014
Y1 - 2014
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
AB - 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
U2 - https://doi.org/10.1002/humu.22538
DO - https://doi.org/10.1002/humu.22538
M3 - Article
C2 - 24599544
SN - 1059-7794
VL - 35
SP - 521
EP - 531
JO - Human mutation
JF - Human mutation
IS - 5
ER -