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

Abstract

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.

Deficiency in the mRNA export mediator Gle1 impairs Schwann cell development in the zebrafish embryo

“…6). This phenotype resembles that observed in adcy6 morpholino mutants (morphants), where greatly reduced mbp expression was observed along the PLLn in spite of apparently normal expression of markers for PLLn axons and Schwann cell precursors (Laquérriere et al, 2014).…”

“…PIPKIγ phosphorylates phosphatidylinositol 4-phosphate to generate phosphatidylinositol-4,5-bisphosphate (PIP 2 ) and the localized synthesis of PIP 2 is important for asymmetric process retraction during directional Schwann cell migration (Gatto et al, 2007). Dynamin 2 is involved in clathrin-mediated endocytosis and required for Schwann cell myelination (Sidiropoulos et al, 2012), CNTNAP1 is an essential component of Ranvier domains, while knockdown of ADCY6 orthologues in zebrafish blocked PNS myelination (Laquérriere et al, 2014). GLE1 function has not been associated with PNS myelination, however RNA expression profiling of spinal cord from LCCS1 fetuses indicated that oligodendrocyte dysfunction may be a factor in disease pathogenesis (Pakkasjarvi et al, 2006).…”

Molecular etiology of arthrogryposis in multiple families of mostly Turkish origin

“…The common findings in these patients were prenatally detected restriction of movements; craniofacial dysmorphisms, including down-slanting palpebral fissures, low-set ears, and micrognathia; and multiple contractures of the limbs ( Figure 2B). The distribution of CHRNG mutations detected in our study is shown in Figure 2, C and D. Two of the identified CHRNG mutations have not been reported, while the other mutations, including the recurrent mutation, have been reported previously in MPS patients (20,36). In 1 of 3 patients with the same homozygous CHRNG mutation (BAB5611), we additionally identified another homozygous deleterious mutation in a different arthrogryposis gene, ERCC2 (c.1775G>A; p.Arg592His) (Figure 2A Other identified variants in known genes are delineated in Tables 1 and 2.…”

Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy

“…Previously, seven patients with CNTNAP1 frameshift variants from four consanguineous families were reported. 7 All nine patients shared common features namely polyhydramnios, fetal akinesia, severe neonatal hypotonia, facial diplegia, absence of swallowing and of spontaneous breathing and arthrogryposis. The most striking feature in our patients was generalized hypotonia.…”