UBR1 – Johanson-Blizzard Syndrome

Johanson-Blizzard syndrome (JBS) is a rare autosomal recessive disorder caused by loss-of-function mutations in UBR1, encoding a ubiquitin ligase of the N-end rule pathway. Clinically, JBS is defined by congenital exocrine pancreatic insufficiency, hypoplastic or aplastic nasal alae, scalp defects, growth retardation, intellectual disability and hypothyroidism. The disease locus was mapped to chromosome 15q15–21.1, and pathogenic UBR1 variants have been identified in multiple unrelated families (PMID:16311597).

Genetic evidence for UBR1-JBS is compelling. In a cohort of 12 unrelated families, truncating and splice-site mutations abolished UBR1 expression in patient pancreatic tissue and segregated with disease (PMID:16311597). Subsequent reports describe over 60 molecularly confirmed cases, including novel homozygous nonsense variants such as c.3682C>T (p.Gln1228Ter) in gender-discordant twins (PMID:25036160), compound heterozygous missense and splice variants identified by exome sequencing, and multi-exon deletions detected via MLPA (PMID:29178640).

The variant spectrum encompasses nonsense, frameshift, splice-site, missense and small in-frame deletions. Notable examples include c.4027_4028del (p.Leu1343ValfsTer7) in a 2-month-old infant (PMID:35769968) and c.1280T>G (p.Leu427Arg) in a mild phenotype without intellectual disability (PMID:26149651). Hypomorphic alleles correlate with attenuated phenotypes, while truncating variants result in classic JBS.

Functional studies substantiate UBR1 haploinsufficiency. UBR1-null pancreatic tissue from patients exhibits intrauterine-onset destructive pancreatitis, and Ubr1−/− mice recapitulate exocrine insufficiency and malformations (PMID:16311597). Yeast modeling of patient missense alleles in the UBR box and RING-H2 domains confirms loss or reduction of ubiquitin-ligase activity, mirroring clinical severity (PMID:21931868). Crystal structures of the human UBR1 UBR box reveal unfolding and loss of peptide binding for a pathogenic missense mutant, elucidating the molecular mechanism (PMID:20835242).

No credible reports dispute the UBR1–JBS association. Phenotypic variability is attributable to allele-specific residual activity rather than alternative genetic causes. There is a clear genotype–phenotype correlation distinguishing hypomorphic from null alleles.

In summary, extensive segregation in consanguineous and unrelated families, a broad variant spectrum, and robust functional concordance in cellular and animal models establish a definitive gene-disease relationship. Key take-home: UBR1 molecular testing is essential for accurate diagnosis, management and genetic counseling in JBS.

References

• Nature Genetics • 2005 • Deficiency of UBR1, a ubiquitin ligase of the N-end rule pathway, causes pancreatic dysfunction, malformations and mental retardation (Johanson-Blizzard syndrome) PMID:16311597
• Genetics and Molecular Research • 2014 • Case report. Johanson-Blizzard syndrome: a report of gender-discordant twins with a novel UBR1 mutation PMID:25036160
• Molecular Genetics & Genomic Medicine • 2017 • Expanding the mutational spectrum in Johanson-Blizzard syndrome: identification of whole exon deletions and duplications in the UBR1 gene by multiplex ligation-dependent probe amplification analysis PMID:29178640
• Genetics and Molecular Research • 2015 • Two novel UBR1 gene mutations in a patient with Johanson Blizzard Syndrome: A mild phenotype without mental retardation PMID:26149651
• Journal of Pediatric Genetics • 2022 • Johanson-Blizzard's Syndrome with a Novel UBR1 Mutation PMID:35769968
• PLoS One • 2011 • Ubiquitin ligases of the N-end rule pathway: assessment of mutations in UBR1 that cause the Johanson-Blizzard syndrome PMID:21931868
• Nature Structural & Molecular Biology • 2010 • Structural basis of substrate recognition and specificity in the N-end rule pathway PMID:20835242

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