INSERM Unité 983, Service de Néphrologie Pédiatrique, Hôpital Necker–Enfants Malades, Assistance Publique–Hôpitaux de Paris, Paris, France.
N Engl J Med. 2011 Dec 22;365(25):2377-88. doi: 10.1056/NEJMoa1109122.
Charcot-Marie-Tooth neuropathy has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, the common mechanisms underlying the neuropathy and FSGS remain unknown. Mutations in INF2 were recently identified in patients with autosomal dominant 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. We therefore hypothesized that INF2 may be responsible for cases of Charcot-Marie-Tooth neuropathy associated with FSGS.
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. Histologic and functional studies were also conducted.
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. Patients presented with an intermediate form of Charcot-Marie-Tooth neuropathy as well as a glomerulopathy with FSGS on kidney biopsy. Immunohistochemical analysis revealed strong INF2 expression in Schwann-cell cytoplasm and podocytes. Moreover, we demonstrated that INF2 colocalizes and interacts with MAL in Schwann cells. 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.
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. These findings provide new insights into the pathophysiological mechanisms linking formin proteins to podocyte and Schwann-cell function. (Funded by the Agence Nationale de la Recherche and others.).
Charcot-Marie-Tooth 神经病与肾脏疾病有关，主要是局灶性节段性肾小球硬化症（FSGS）。然而，神经病和 FSGS 的共同机制尚不清楚。最近在常染色体显性 FSGS 患者中发现了 INF2 的突变。INF2 编码一种形成蛋白，与 Rho-GTPase CDC42 和少突胶质细胞-淋巴细胞蛋白（MAL）相互作用，这些蛋白参与髓鞘形成和髓鞘维持的基本步骤。因此，我们假设 INF2 可能是导致伴有 FSGS 的 Charcot-Marie-Tooth 神经病的原因。
我们对 16 名无 PMP22 或 MPZ 突变的 Charcot-Marie-Tooth 神经病和 FSGS 指数患者进行了 INF2 的直接基因分型，PMP22 和 MPZ 分别编码外周髓鞘蛋白 22 和髓鞘蛋白零。还进行了组织学和功能研究。
我们在 16 名指数患者中的 12 名（75%）中发现了 9 个新的杂合突变，均位于编码 INF2 的 diaphanous-inhibitory 结构域的外显子 2 和 3 中。患者表现为中间型 Charcot-Marie-Tooth 神经病以及肾活检中的 FSGS 肾小球病。免疫组织化学分析显示 Schwann 细胞细胞质和足细胞中存在强烈的 INF2 表达。此外，我们证明 INF2 与 MAL 在 Schwann 细胞中相互作用。INF2 突变体扰乱了 INF2-MAL-CDC42 途径，导致细胞骨架紊乱，增强了 INF2 与 CDC42 的结合以及 INF2、MAL 和 CDC42 的定位错误。
INF2 突变似乎导致许多伴有 FSGS 的 Charcot-Marie-Tooth 神经病，表明 INF2 参与了影响肾脏肾小球和周围神经系统的疾病。这些发现为连接形成蛋白与足细胞和 Schwann 细胞功能的病理生理机制提供了新的见解。（由法国国家研究署等资助）。
