![]() ![]() 1 Affected persons typically present with progressive distal-muscle weakness and atrophy, reduced tendon reflexes, and foot and hand deformities. (Funded by the Agence Nationale de la Recherche and others.) IntroductionĬharcot–Marie–Tooth disease refers to a heterogeneous group of inherited chronic peripheral motor and sensory neuropathies. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. INF2 mutations appear to cause many cases of FSGS-associated Charcot–Marie–Tooth neuropathy, showing that INF2 is involved in a disease affecting both the kidney glomerulus and the peripheral nervous system. The INF2 mutants perturbed the INF2–MAL–CDC42 pathway, resulting in cytoskeleton disorganization, enhanced INF2 binding to CDC42 and mislocalization of INF2, MAL, and CDC42. ![]() Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Patients presented with an intermediate form of Charcot–Marie–Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. We identified nine new heterozygous mutations in 12 of the 16 index patients (75%), all located in exons 2 and 3, encoding the diaphanous-inhibitory domain of INF2. Histologic and functional studies were also conducted. We performed direct genotyping of INF2 in 16 index patients with Charcot–Marie–Tooth neuropathy and FSGS who did not have a mutation in PMP22 or MPZ, encoding peripheral myelin protein 22 and myelin protein zero, respectively. We therefore hypothesized that INF2 may be responsible for cases of Charcot–Marie–Tooth neuropathy associated with FSGS. INF2 encodes a formin protein that interacts with the Rho-GTPase CDC42 and myelin and lymphocyte protein (MAL) that are implicated in essential steps of myelination and myelin maintenance. Mutations in INF2 were recently identified in patients with autosomal dominant FSGS. However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Original Article INF2 Mutations in Charcot–Marie–Tooth Disease with Glomerulopathy List of authors.Ĭharcot–Marie–Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). The most trusted, influential source of new medical knowledge and clinical best practices in the world. Information and tools for librarians about site license offerings. Valuable tools for building a rewarding career in health care. The authorized source of trusted medical research and education for the Chinese-language medical community. The most advanced way to teach, practice, and assess clinical reasoning skills. Information, resources, and support needed to approach rotations - and life as a resident. The most effective and engaging way for clinicians to learn, improve their practice, and prepare for board exams. NEW! Peer-reviewed journal featuring in-depth articles to accelerate the transformation of health care delivery.Ĭoncise summaries and expert physician commentary that busy clinicians need to enhance patient care. NEW! A digital journal for innovative original research and fresh, bold ideas in clinical trial design and clinical decision-making. ![]()
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