Hytönen Marjo K, Rönkkö Julius, Hundi Sruthi, Jokinen Tarja S, Suonto Emilia, Teräväinen Eeva, Donner Jonas, La Rovere Rita, Bultynck Geert, Ylikallio Emil, Tyynismaa Henna, Lohi Hannes
Department of Veterinary Biosciences, Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland.
Department of Medical and Clinical Genetics, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
PLoS Genet. 2025 Jan 13;21(1):e1011328. doi: 10.1371/journal.pgen.1011328. eCollection 2025 Jan.
Inositol 1,4,5-trisphosphate receptors (IP3R) mediate Ca2+ release from intracellular stores, contributing to complex regulation of numerous physiological responses. The involvement of the three IP3R genes (ITPR1, ITPR2 and ITPR3) in inherited human diseases has started to shed light on the essential roles of each receptor in different human tissues and cell types. Variants in the ITPR3 gene, which encodes IP3R3, have recently been found to cause demyelinating sensorimotor Charcot-Marie-Tooth neuropathy type 1J (CMT1J). In addition to peripheral neuropathy, immunodeficiency and tooth abnormalities are occasionally present. Here, we report the identification of a homozygous nonsense variant in the ITPR3 gene in Lancashire Heeler dogs, presenting with a severe developmental enamel defect and reduced nerve conduction velocity. We studied the primary skin fibroblasts of the affected dogs and observed that the nonsense variant in ITPR3 led to a complete absence of full-length IP3R3 protein. Unexpectedly, the protein levels of IP3R1 and IP3R2 were also markedly decreased, suggesting co-regulation. Functional Ca2+ measurements revealed reduced IP3R-mediated Ca2+ flux upon stimulation of G-protein-coupled-receptors in the affected dog fibroblasts. These findings highlight the first spontaneous mammalian phenotype caused by a nonsense variant in ITPR3, leading to the loss of IP3R3. The human and canine IP3R3 proteins are highly similar, and our study suggests that the tissue involvement resulting from the receptor's dysfunction is also conserved. In summary, IP3R3 is critical for enamel formation and peripheral nerve maintenance.
肌醇1,4,5 - 三磷酸受体（IP3R）介导细胞内钙库释放Ca2+，参与众多生理反应的复杂调节。三个IP3R基因（ITPR1、ITPR2和ITPR3）在人类遗传性疾病中的作用，已开始揭示每个受体在不同人体组织和细胞类型中的重要作用。最近发现，编码IP3R3的ITPR3基因变异会导致1J型脱髓鞘感觉运动性夏科 - 马里 - 图斯神经病（CMT1J）。除了周围神经病变外，偶尔还会出现免疫缺陷和牙齿异常。在此，我们报告在兰开夏赫勒犬中鉴定出ITPR3基因的纯合无义变异，该犬表现出严重的发育性釉质缺陷和神经传导速度降低。我们研究了患病犬的原代表皮成纤维细胞，观察到ITPR3中的无义变异导致全长IP3R3蛋白完全缺失。出乎意料的是，IP3R1和IP3R2的蛋白水平也显著降低，提示存在共同调节。功能性Ca2+测量显示，在受影响的犬成纤维细胞中，刺激G蛋白偶联受体后，IP3R介导的Ca2+通量降低。这些发现突出了由ITPR3中的无义变异导致IP3R3缺失所引起的首个自发性哺乳动物表型。人和犬的IP3R3蛋白高度相似，我们的研究表明受体功能障碍导致的组织受累情况也是保守的。总之，IP3R3对釉质形成和周围神经维持至关重要。
