Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects

Hum Mol Genet. 2014 May 1;23(9):2279-89. doi: 10.1093/hmg/ddt618. Epub 2013 Dec 6.


Non-syndromic arthrogryposis multiplex congenita (AMC) is characterized by multiple congenital contractures resulting from reduced fetal mobility. Genetic mapping and whole exome sequencing (WES) were performed in 31 multiplex and/or consanguineous undiagnosed AMC families. Although this approach identified known AMC genes, we here report pathogenic mutations in two new genes. Homozygous frameshift mutations in CNTNAP1 were found in four unrelated families. Patients showed a marked reduction in motor nerve conduction velocity (<10 m/s) and transmission electron microscopy (TEM) of sciatic nerve in the index cases revealed severe abnormalities of both nodes of Ranvier width and myelinated axons. CNTNAP1 encodes CASPR, an essential component of node of Ranvier domains which underlies saltatory conduction of action potentials along the myelinated axons, an important process for neuronal function. A homozygous missense mutation in adenylate cyclase 6 gene (ADCY6) was found in another family characterized by a lack of myelin in the peripheral nervous system (PNS) as determined by TEM. Morpholino knockdown of the zebrafish orthologs led to severe and specific defects in peripheral myelin in spite of the presence of Schwann cells. ADCY6 encodes a protein that belongs to the adenylate cyclase family responsible for the synthesis of cAMP. Elevation of cAMP can mimic axonal contact in vitro and upregulates myelinating signals. Our data indicate an essential and so far unknown role of ADCY6 in PNS myelination likely through the cAMP pathway. Mutations of genes encoding proteins of Ranvier domains or involved in myelination of Schwann cells are responsible for novel and severe human axoglial diseases.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylyl Cyclases / genetics*
  • Arthrogryposis / genetics*
  • Arthrogryposis / pathology*
  • Axons / pathology
  • Axons / ultrastructure
  • Cell Adhesion Molecules, Neuronal / genetics*
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Microscopy, Electron, Transmission
  • Mutation / genetics
  • Myelin Sheath / pathology
  • Peripheral Nervous System / pathology
  • Peripheral Nervous System / ultrastructure
  • Pregnancy
  • Schwann Cells / metabolism


  • CNTNAP1 protein, human
  • Cell Adhesion Molecules, Neuronal
  • Adenylyl Cyclases
  • adenylyl cyclase 6