Mutations in the HumanUBR1Gene 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.

Pathogenic variants in E3 ubiquitin ligase RLIM/RNF12 lead to a syndromic X-linked intellectual disability and behavior disorder

“…Its dysregulation leads to various movement disturbances, dementia and hypogonadotropic hypogonadism [44,45]. Thus, it is not surprising that a growing group of ID proteins are directly involved in UPS-mediated protein degradation, such as UBE3A [46] [47], UBE2A [48,49,50,51], UBE3B [52,47], HUWE1 [53,54,55], MID1 [56][57][58][59], CUL4B [60,[61][62][63], UBR1 [64,65,66], TRIP12 [67][68][69], and RNF216 [45,[70][71][72].…”

Spectrum of Clinical and Associated MR Imaging Findings in Children with Olfactory Anomalies

“…The gene encodes for a protein involved in many basic biologic functions including neurogenesis and has been associated with absent OBs. 30 The patient with Jacobsen syndrome had an 11q23.3 deletion and additional genetic abnormalities. Patients typically have facial dysmorphism, thrombocytopenia, and multiple malformations that include the CNS.…”

Two novel UBR1 gene mutations ın a patient with Johanson Blizzard Syndrome: A mild phenotype without mental retardation

“…This gene contains 47 exons spanning 161 kb (Zenker et al, 2005;Sukalo et al, 2014). One of the E3 ubiquitin ligases of the N-end rule pathway is encoded by UBR1 and this pathway is thought to be responsible for protein degradation, and regulated protein destruction (Rezaei et al, 2011).…”

“…The cardinal features of JBS are exocrine pancreatic insufficiency, an abnormal facial appearance with a small beak-like nose, scalp defects, sensorineural hearing loss, hypothyroidism and varying degrees of mental retardation (Johanson and Blizzard, 1971;Hurst and Baraitser, 1989). Since JBS was first described by Ann Johanson and Robert Blizzard in 1971, more than 60 patients have been reported in the literature (Johanson and Blizzard, 1971;Sukalo et al, 2014). The prevalence of JBS in Europe has been estimated at 1/250,000 (Zenker et al, 2005).…”

“…1) (Kwon et al, 1998;Sukalo et al, 2014). This protein represents one of at least four E3 ubiquitin ligases of the N-end rule pathway.…”