Biallelic variants in ARHGAP19 cause a progressive inherited motor-predominant neuropathy [2026]
Küçük Resim Yok
Tarih
2026
Dergi Başlığı
Dergi ISSN
Cilt Başlığı
Yayıncı
American Society for Clinical Investigation
Erişim Hakkı
info:eu-repo/semantics/openAccess
Özet
Charcot-Marie-Tooth (CMT) disease is a clinically and genetically heterogeneous group of hereditary neuropathies. Despite progress in genetic sequencing, for around a quarter of patients the disease has lacked a genetic explanation. Here, we identified 16 recessive variants in the RhoGTPase activating protein 19 gene (ARHGAP19) causing motor-predominant neuropathy in 25 individuals from 20 unrelated families. The ARHGAP19 protein acts as a negative regulator of the RhoA GTPase. In vitro biochemical and cellular assays revealed that patient variants impair the GTPase-activating protein (GAP) activity of ARHGAP19 and reduce ARHGAP19 protein levels. Through the use of patient lines, in vitro GAP assays and in silico molecular modeling, we provided evidence that CMT-associated ARHGAP19 variants act through a loss-of-function (LOF) mechanism. LOF in ARHGAP19 orthologues in Drosophila melanogaster and Danio rerio induced motor defects in axonal and synaptic morphology. Similar cellular phenotypes were observed in ARHGAP19 patient-derived motoneurons. Transcriptomic studies further demonstrated that ARHGAP19 regulates cellular pathways associated with motor proteins and the cell cycle. Taken together, our findings establish ARHGAP19 variants as a cause of inherited neuropathy acting through a LOF mechanism. © 2025, Dominik et al.
Açıklama
Anahtar Kelimeler
guanine nucleotide binding protein, Rho guanine nucleotide binding protein activating protein 19, unclassified drug, adolescent, adult, animal experiment, animal model, animal tissue, ARHGAP19 gene, Article, autosomal recessive inheritance, cell migration, cell proliferation, Charcot Marie Tooth disease intermediate, Charcot Marie Tooth disease type 2, child, clinical article, clinical feature, computer model, controlled study, Drosophila melanogaster, embryo, family, female, fibroblast, gene, genetic variability, hereditary motor neuropathy, hereditary motor sensory neuropathy, human, human cell, in vitro study, in vivo study, induced pluripotent stem cell, locomotion, loss of function mutation, male, middle aged, molecular model, motoneuron, nonhuman, orthology, phenotype, rat, school child, transcriptomics, young adult, zebra fish
Kaynak
Journal of Clinical Investigation
WoS Q Değeri
Scopus Q Değeri
Q1
Cilt
136
Sayı
3
