IP3 receptor depletion in a spontaneous canine model of Charcot-Marie-Tooth disease 1J with amelogenesis imperfecta

• DOI: 10.1371/journal.pgen.1011328
• Publication Date: 2025-01-13T19:06:49Z
• Authors: Marjo K. Hytönen; Julius Rönkkö; Sruthi Hundi; Tarja S. Jokinen; Emilia Suonto; Eeva Teräväinen; Jonas Donner; Rita La Rovere; Geert Bultynck; Emil Ylikallio; Henna Tyynismaa; Hannes Lohi
• Keywords: Amelogenesis imperfecta; Tooth disease; Amelogenesis

Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started shed light on essential roles each receptor different tissues cell types. Variants ITPR3 gene, which encodes IP3R3, have recently been found cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition peripheral neuropathy, immunodeficiency tooth abnormalities are occasionally present. Here, we report identification a homozygous nonsense variant gene Lancashire Heeler dogs, presenting with severe developmental enamel defect reduced nerve conduction velocity. We studied primary skin fibroblasts affected dogs observed that led complete absence full-length IP3R3 protein. Unexpectedly, protein levels IP3R1 IP3R2 were also markedly decreased, suggesting co-regulation. Functional measurements revealed IP3R-mediated flux upon stimulation G-protein-coupled-receptors dog fibroblasts. These findings highlight first spontaneous mammalian phenotype caused by ITPR3, leading loss IP3R3. canine proteins highly similar, our study suggests tissue resulting receptor's dysfunction is conserved. summary, critical for formation maintenance.