Mutations in GLDN, Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis

作者：Maluenda Jerome; 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; Laquerriere Annie; Devaux Jerome; Melki Judith^*

来源：American Journal of Human Genetics, 2016, 99(4): 928-933.

DOI：10.1016/j.ajhg.2016.07.021

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.

• 出版日期2016-10-6