Mutations in GLDN , Encoding Gliomedin, a Critical Component of the Nodes of Ranvier, Are Responsible for Lethal Arthrogryposis
The American Journal of Human Genetics. 2016-10-01; 99(4): 928-933
DOI: 10.1016/j.ajhg.2016.07.021
Lire sur PubMed
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.