IVNS1ABP deficiency as the cause of a new progeroid disease

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FBXO22 deficiency causes a congenital syndrome with multisystem involvement

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LATS1-deficiency as a cause of ID & hearing loss

Hallermann-Streiff syndrome goes epigenetic.

IVNS1ABP Deficiency Disrupts Actin Filament Organization and Leads to Cellular Senescence in a Newly Identified Progeroid Neuropathy Syndrome

 Fang Yuan, Ye Sing Tan, Haofei Wang, Ain Nur Ali, Qiang Yuan, Shu-Min Chou, Yu-Hsin Yen, Gunaseelan Narayanan, Lei Zhou, Mohammad Shboul, Carine Bonnard,  Bruno Reversade,  Su-Chun Zhang

A homozygous variant in IVNS1ABP was identified in three siblings, displaying progeroid features with severe neuropathy. By generating isogenic induced pluripotent stem cells (iPSCs) from the patients’ fibroblasts and differentiating the iPSCs into neural progenitor cells (NPCs), we found that mutant IVNS1ABP fibroblasts, iPSCs, and NPCs exhibited disrupted cytokinesis, DNA damage and cellular senescence. Correspondingly, cerebral organoids displayed premature differentiation of NPCs to neurons. Molecular profiling as well as biochemical and cellular analysis revealed altered binding of mutant IVNS1ABP to actin /actin-associated proteins and dysregulated actin dynamics during cytokinesis. Taken together, we propose that mutant IVNS1ABP dysregulates actin polymerization and organization which is at least partly responsible for the cellular senescence phenotypes in this progeroid neuropathy syndrome. 

Loss of IVNS1ABP, a gigaxonin paralogue, leads to a progeroid neuropathy due to impaired proteostasis

CCarine Bonnard, Ain Nur Ali, Fang Yuan, Kiat Y. Tan, Yan T. Lim, Puck W. Chan, Nanthini Ramanathan, Nur A.B.M. Kamsani, Vindhya Chaganty, Ding Xiong, Ye S. Tan, Shu-Min Chou, Marwa Chourabi, Gunaseelan Narayanan, Alvin Y.J. Ng, Sumanty Tohari, Meah W. Yang, Birsen Karaman, Gözde T. Turgut, Emmanuelle Szenker-Ravi, Radoslaw M. Sobota, Zhuoyao Chen, Alex N. Bullock, Rajaa Fathallah, Umut Altunoglu, Venkatesh Byrappa, Ajay S. Mathuru, Mohammad Shboul, Su-Chun Zhang,  Bruno Reversade

Impaired proteostasis can induce protein aggregation which is toxic to neuronal cells, contributing to neurodegeneration and other signs of aging. In this study, we delineate an early-onset progressive neuropathy evoking Giant Axonal Neuropathy 1. The causative gene IVNS1ABP encodes a E3-ubiquitin ligase adaptor which is a close gigaxonin paralogue. Patient-derived fibroblasts, iPSCs, and neural progenitors exhibited hallmarks of protein accumulation and lysosomal dysfunction. Ubiquitome analysis revealed overlapping targets with gigaxonin, including Vimentin and MAP1B. The biallelic correction to the isogenic wildtype state in disease- relevant motor neurons partly rescued cellular vulnerabilities. A newly generated ivns1abpa/b knockout zebrafish model partially recapitulated the human peripheral neuropathy, exhibiting aberrant primary motor neuron axon pathfinding, leading to impaired locomotion. Our findings indicate that IVNS1ABP functions in the same pathway as gigaxonin, ensuring appropriate cellular turnover of critical protein substrates, whose accumulation leads to accelerated aging in discrete cellular lineages.