<i>COPB2</i>haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Marom, Ronit; Burrage, Lindsay C.; Clément, Aurélie; Blanco-Sánchez, Bernardo; Venditti, Rossella; Jain, Mahim; Grafe, Ingo; Scott, Daryl A.; Rosenfeld, Jill A.; Sutton, V. Reid; Shinawi, Marwan; Mirzaa, Ghayda; DeVile, Catherine; Roberts, Rowenna; Calder, Alistair; Allgrove, Jeremy; Lanza, Denise G.; Li, Xiaohui; Joeng, Kyu Sang; Lee, Yi-Chien; Song, I-Wen; Sliepka, Joseph M.; Batkovskyte, Dominyka; Jin, Zixue; Dawson, Brian; Chen, Shan; Chen, Yuqing; Jiang, Mingming; Munivez, Elda; Tran, Alyssa A.; Emrick, Lisa; Murdock, David R.; Hanchard, Neil A.; Zapata, Gladys; Mehta, Nitesh R; Weis, Mary Ann; Kuzawa, Cole; Scott, Abbey; Tremp, Brenna A.; Phillips, Jennifer B.; Wegner, Jeremy; Taylor-Miller, Tashunka; Gibbs, Richard A.; Jhangiani, Shalini N.; Stottmann, Rolf; Dickinson, Mary E.; Seavitt, John R.; Heaney, Jason D.; Eyre, David W; Ambrose, Catherine G.; Matteis, Maria Antonella De; Lee, Brendan

doi:10.1101/2020.09.14.297234

Cited by 2 publications

(1 citation statement)

References 52 publications

(70 reference statements)

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“…ER stress plays a complex role in the induction of inflammation (20). Defects in the retrograde Golgi-to-ER transport caused by mutations in different COPI subunit proteins, were previously described to result in an increased ER stress (27,(32)(33)(34)(35). Similarly, we observed an increased ER stress specifically in CDC42 R186C.…”

Section: Discussionsupporting

confidence: 65%

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation

Iannuzzo,

Delafontaine,

Masri

et al. 2024

Preprint

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Most autoinflammatory diseases are caused by mutations in innate immunity genes. Recently, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports, and endoplasmic reticulum stress. Consequently, it favors STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. Thus, we report new mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.

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Section: Discussionsupporting

confidence: 65%

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation

Iannuzzo,

Delafontaine,

Masri

et al. 2024

Preprint

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Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision

Baldridge

Wangler

Bowman

et al. 2021

Orphanet J Rare Dis

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Decreased sequencing costs have led to an explosion of genetic and genomic data. These data have revealed thousands of candidate human disease variants. Establishing which variants cause phenotypes and diseases, however, has remained challenging. Significant progress has been made, including advances by the National Institutes of Health (NIH)-funded Undiagnosed Diseases Network (UDN). However, 6000–13,000 additional disease genes remain to be identified. The continued discovery of rare diseases and their genetic underpinnings provides benefits to affected patients, of whom there are more than 400 million worldwide, and also advances understanding the mechanisms of more common diseases. Platforms employing model organisms enable discovery of novel gene-disease relationships, help establish variant pathogenicity, and often lead to the exploration of underlying mechanisms of pathophysiology that suggest new therapies. The Model Organism Screening Center (MOSC) of the UDN is a unique resource dedicated to utilizing informatics and functional studies in model organisms, including worm (Caenorhabditis elegans), fly (Drosophila melanogaster), and zebrafish (Danio rerio), to aid in diagnosis. The MOSC has directly contributed to the diagnosis of challenging cases, including multiple patients with complex, multi-organ phenotypes. In addition, the MOSC provides a framework for how basic scientists and clinicians can collaborate to drive diagnoses. Customized experimental plans take into account patient presentations, specific genes and variant(s), and appropriateness of each model organism for analysis. The MOSC also generates bioinformatic and experimental tools and reagents for the wider scientific community. Two elements of the MOSC that have been instrumental in its success are (1) multidisciplinary teams with expertise in variant bioinformatics and in human and model organism genetics, and (2) mechanisms for ongoing communication with clinical teams. Here we provide a position statement regarding the central role of model organisms for continued discovery of disease genes, and we advocate for the continuation and expansion of MOSC-type research entities as a Model Organisms Network (MON) to be funded through grant applications submitted to the NIH, family groups focused on specific rare diseases, other philanthropic organizations, industry partnerships, and other sources of support.

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COPB2haploinsufficiency causes a coatopathy with osteoporosis and developmental delay

Cited by 2 publications

References 52 publications

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation

Model organisms contribute to diagnosis and discovery in the undiagnosed diseases network: current state and a future vision

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