Johanson-Blizzard syndrome (JBS), also known as UBR1-related disorder, is a very rare autosomal recessive disorder caused by pathogenic variants in the UBR1 gene and characterized by significant phenotypic variability. The condition is known to be mainly characterized by craniofacial abnormalities, exocrine pancreatic insufficiency, growth retardation, and sensorineural hearing loss. We describe three affected siblings from a consanguineous Yemeni family with JBS. Two brothers suffered from profound symptoms resulting in infant death, which included failure to thrive, exocrine pancreatic dysfunction, anemia, hypoalbuminemia, aplasia cutis congenita, and cardiomyopathy, which was only present in one sibling. The third sibling, who is still alive, is a one-year-old girl who presented with vomiting, diarrhea, failure to thrive, and marked facial dysmorphic features, including hypoplastic alae nasi, a beaked nose, brachycephaly, and a fifth-finger anomaly, without significant visceral malformations. Genome analysis of the affected sibling revealed a homozygous missense mutation in the UBR1 gene, following the American College of Medical Genetics and Genomics (ACMG) guidelines. Moreover, the familial form, consanguinity, and typical presentation are highly suggestive of a diagnosis of JBS. The current case report draws attention to the significant variability of JBS within families and, once again, emphasizes the need for precise clinical assessment in order to make a diagnosis, especially when molecular testing might be equivocal in resource-poor environments. Early multidisciplinary supportive care and genetic counseling are pivotal for optimizing patient survival and minimizing the rate of recurrence within affected kindreds. A narrative review of the literature was conducted to contextualize the clinical findings and highlight intrafamilial phenotypic variability.

Johanson-Blizzard syndrome (JBS) is an exceedingly rare, autosomal recessively inherited disorder. It affects both males and females equally. Exocrine pancreatic insufficiency is the most common finding of the syndrome. The clinical presentation varies significantly among cases. A 6-month-old infant was referred due to persistent diarrhea and failure to gain weight. The diagnosis of JBS was made based on family history and medical investigations; pancreatic enzymes (Pancreatin) were the first line of therapy besides the fluids, blood transfusions, and vitamins. The exact cause of death remains unclear. This case highlights the severe systemic nature of JBS. Early recognition and comprehensive management are crucial for improving outcomes.

The Johanson-Blizzard syndrome (JBS) is a complex autosomal recessive disorder that manifests through a spectrum of symptoms, with deficiencies in the ubiquitin-protein ligase E3 component N-recognin 1 (UBR-1) at its genetic core. Despite its clinical significance, the molecular intricacies of UBR-1's role in JBS remain largely elusive, presenting a formidable challenge in devising targeted treatments. The nematode Caenorhabditis elegans, with its genetic tractability and conservation of fundamental biological mechanisms, emerges as an invaluable model for unravelling the molecular underpinnings of JBS. This review integrates the latest discoveries from C. elegans studies, shedding light on UBR-1's multiple functions: its regulatory impact on cellular pathways and, particularly, its crucial involvement in glutamate metabolism. By assessing the contributions of these studies to our understanding of JBS, this review highlights the potential significance of glutamate metabolic dysfunction in JBS pathogenesis.

E3 ubiquitin ligases have been linked to developmental diseases including autism, Angelman syndrome (UBE3A), and Johanson-Blizzard syndrome (JBS) (UBR1). Here, we report variants in the E3 ligase UBR5 in 29 individuals presenting with a neurodevelopmental syndrome that includes developmental delay, autism, intellectual disability, epilepsy, movement disorders, and/or genital anomalies. Their phenotype is distinct from JBS due to the absence of exocrine pancreatic insufficiency and the presence of autism, epilepsy, and, in some probands, a movement disorder. E3 ubiquitin ligases are responsible for transferring ubiquitin to substrate proteins to regulate a variety of cellular functions, including protein degradation, protein-protein interactions, and protein localization. Knocking out ubr-5 in C. elegans resulted in a lower movement score compared to the wild type, supporting a role for UBR5 in neurodevelopment. Using an in vitro autoubiquitination assay and confocal microscopy for the human protein, we found decreased ubiquitination activity and altered cellular localization in several variants found in our cohort compared to the wild type. In conclusion, we found that variants in UBR5 cause a neurodevelopmental syndrome that can be associated with a movement disorder, reinforcing the role of the UBR protein family in a neurodevelopmental disease that differs from previously described ubiquitin-ligase-related syndromes. We also provide evidence for the pathogenic potential loss of UBR5 function with functional experiments in C. elegans and in vitro ubiquitination assays.

Johanson-Blizzard Syndrome (JBS) is an autosomal recessive spectrum disorder associated with the UBR-1 ubiquitin ligase that features developmental delay including motor abnormalities. Here, we demonstrate that C. elegans UBR-1 regulates high-intensity locomotor behavior and developmental viability via both ubiquitin ligase and scaffolding mechanisms. Super-resolution imaging with CRISPR-engineered UBR-1 and genetic results demonstrated that UBR-1 is expressed and functions in the nervous system including in pre-motor interneurons. To decipher mechanisms of UBR-1 function, we deployed CRISPR-based proteomics using C. elegans which identified a cadre of glutamate metabolic enzymes physically associated with UBR-1 including GLN-3, GOT-2.2, GFAT-1 and GDH-1. Similar to UBR-1, all four glutamate enzymes are genetically linked to human developmental and neurological deficits. Proteomics, multi-gene interaction studies, and pharmacological findings indicated that UBR-1, GLN-3 and GOT-2.2 form a signaling axis that regulates glutamate homeostasis. Developmentally, UBR-1 is expressed in embryos and functions with GLN-3 to regulate viability. Overall, our results suggest UBR-1 is an enzyme hub in a GOT-2.2/UBR-1/GLN-3 axis that maintains glutamate homeostasis required for efficient locomotion and organismal viability. Given the prominent role of glutamate within and outside the nervous system, the UBR-1 glutamate homeostatic network we have identified could contribute to JBS etiology.