Maluenda Jérôme, Manso Constance, Quevarec Loic, Vivanti Alexandre, Marguet Florent, Gonzales Marie, Guimiot Fabien, Petit Florence, Toutain Annick, Whalen Sandra, Grigorescu Romulus, Coeslier Anne Dieux, Gut Marta, Gut Ivo, Laquerrière Annie, Devaux Jérôme, Melki Judith
INSERM UMR-1169, Université Paris Saclay, Le Kremlin Bicêtre 94276, France.
UMR-7286, Centre de Recherche en Neurobiologie et Neurophysiologie de Marseille, Aix-Marseille Université, Centre National de la Recherche Scientifique, Marseille 13444, France.
Am J Hum Genet. 2016 Oct 6;99(4):928-933. doi: 10.1016/j.ajhg.2016.07.021. Epub 2016 Sep 8.
Arthrogryposis multiplex congenita (AMC) is a developmental condition characterized by multiple joint contractures resulting from reduced or absent fetal movements. Through linkage analysis, homozygosity mapping, and exome sequencing in four unrelated families affected by lethal AMC, we identified biallelic mutations in GLDN in the affected individuals. GLDN encodes gliomedin, a secreted cell adhesion molecule involved in the formation of the nodes of Ranvier. Transmission electron microscopy of the sciatic nerve from one of the affected individuals showed a marked lengthening defect of the nodes. The GLDN mutations found in the affected individuals abolish the cell surface localization of gliomedin and its interaction with its axonal partner, neurofascin-186 (NF186), in a cell-based assay. The axoglial contact between gliomedin and NF186 is essential for the initial clustering of Na channels at developing nodes. These results indicate a major role of gliomedin in node formation and the development of the peripheral nervous system in humans. These data indicate that mutations of GLDN or CNTNAP1 (MIM: 616286), encoding essential components of the nodes of Ranvier and paranodes, respectively, lead to inherited nodopathies, a distinct disease entity among peripheral neuropathies.
先天性多发性关节挛缩症（AMC）是一种发育性疾病，其特征是由于胎儿活动减少或缺乏导致多个关节挛缩。通过对四个患有致死性AMC的无关家族进行连锁分析、纯合性定位和外显子组测序，我们在受影响个体中鉴定出GLDN的双等位基因突变。GLDN编码神经胶质素，一种参与郎飞结形成的分泌型细胞粘附分子。对一名受影响个体的坐骨神经进行透射电子显微镜检查显示郎飞结有明显的延长缺陷。在基于细胞的试验中，在受影响个体中发现的GLDN突变消除了神经胶质素的细胞表面定位及其与轴突伴侣神经束蛋白-186（NF186）的相互作用。神经胶质素与NF186之间的轴突-神经胶质接触对于发育中的郎飞结处钠通道的初始聚集至关重要。这些结果表明神经胶质素在人类郎飞结形成和周围神经系统发育中起主要作用。这些数据表明，分别编码郎飞结和结旁结构重要成分的GLDN或CNTNAP1（MIM：616286）突变会导致遗传性结病，这是周围神经病变中的一种独特疾病实体。
