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

Abstract

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.

Nodes, paranodes and neuropathies

“…Here, loss of the transverse bands resulted in paranodal myelin loop detachment and reduced conduction velocities 78. In mouse models mimicking CMT1A79 and 1C,80 paranodal structural changes, including loss of transverse bands and peeling back of myelin loops in the former, or myelin infolding in the latter, are shown to affect conduction and likely contribute to both the demyelination and axonal degeneration seen in these conditions.…”

Genetics of neuromuscular fetal akinesia in the genomics era

“…Features variably included intrauterine growth retardation, knee and elbow contractures, camptodactyly and retrognathia 36. Electron microscopy of one patient’s sciatic nerve showed reduced numbers of myelinated fibres and a significant increase in nodal length.…”

“…Maluenda et al 36 identified six individuals with AMC, marked polyhydramnios and fetal akinesia at 27–32 weeks’ gestation, despite unremarkable earlier ultrasounds. Features variably included intrauterine growth retardation, knee and elbow contractures, camptodactyly and retrognathia 36.…”

“…Electron microscopy of one patient’s sciatic nerve showed reduced numbers of myelinated fibres and a significant increase in nodal length. Biallelic mutations were identified in the gene encoding gliomedin ( GLDN ; MIM 608603), which is an adhesion molecule involved in the formation of the nodes of Ranvier and development of the peripheral nervous system 36. This disorder is designated lethal congenital contracture arthrogryposis 11 (LCCS11; MIM 617194).…”

Loss-of-Function Mutations in LGI4, a Secreted Ligand Involved in Schwann Cell Myelination, Are Responsible for Arthrogryposis Multiplex Congenita

“…Therefore, the biallelic mutations found in the affected individuals of these four families are likely to cause defective signaling of the LGI4 pathway similar to that observed in Lgi4-deficient mice. Recent data indicate that mutations of genes encoding CASPR-1 19 and gliomedin, 20 essential components of the nodes of Ranvier and paranodes, respectively, or proteins involved in myelination of Schwann cells such as ADCY6 19 and GPR126, 21 are responsible for severe human peripheral axoglial diseases, resulting in developmental defect of PNS, hypokinesia, and arthrogryposis. Here, we show that loss-of-function germline mutations of LGI4 leads to a similar phenotype.…”