Alternative titles; symbols
HGNC Approved Gene Symbol: CNTNAP1
Cytogenetic location: 17q21.2 Genomic coordinates (GRCh38): 17:42,682,531-42,699,993 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 17q21.2 | Hypomyelinating neuropathy, congenital, 3 | 618186 | Autosomal recessive | 3 |
| Lethal congenital contracture syndrome 7 | 616286 | Autosomal recessive | 3 |
High-velocity nerve conduction requires that nerve fibers be periodically myelinated by the wrapping of glial cell membranes around the nerve fiber between nodes of Ranvier. Each layer of glial cell membrane contacts the axon at the edge of the node and forms a histologically and functionally distinct subdomain called the paranodal junction. The paranodal junction separates voltage-gated sodium channels at the node of Ranvier from the delayed rectifier potassium channels in the juxtaparanodal region that lies nearer to the densely myelinated region. CNTNAP1 is an essential constituent of a high molecular mass complex in the paranodal junction and is required for high-velocity nerve conduction (summary by Bhat et al. (2001)).
PTPRZ1 (176891) binds to contactin (600016), which is expressed on the surface of neuronal cells, leading to neurite outgrowth and differentiation. Peles et al. (1997) identified a 190-kD protein associated with the contactin-PTPRZ1 complex and cloned the gene based on sequence derived from the purified protein. The 1,384-amino acid protein, designated p190 or CASPR, includes an extracellular domain with several putative protein-protein interaction domains, a putative transmembrane domain, and a 74-amino acid cytoplasmic domain. Northern blot analysis showed that CASPR was transcribed predominantly in brain as a transcript of 6.2 kb, with weak expression in several other tissues tested. Peles et al. (1997) stated that the architecture of the CASPR extracellular domain is similar to that of neurexins (see 600565), and suggested that CASPR is the signaling subunit of contactin, enabling recruitment and activation of intracellular signaling pathways in neurons.
By immunohistochemical analysis, Bhat et al. (2001) detected expression of Cntnap1, which they called Ncp1, at the paranodal region of mouse sciatic nerve and in central nervous system.
Peles et al. (1997) mapped the CASPR gene to chromosome 17q21 on the basis of its inclusion in clones from this region.
Bhat et al. (2001) noted that NCP1 requires interaction with contactin for its surface expression (Faivre-Sarrailh et al., 2000), and that both proteins form a high molecular mass complex in the paranodal junction between glial cell membranes and axons (Rios et al., 2000).
Lethal Congenital Contracture Syndrome 7
By genetic mapping and whole-exome sequencing in 63 patients from 31 multiplex and/or consanguineous families with unexplained nonsyndromic arthrogryposis multiplex congenita, Laquerriere et al. (2014) identified homozygous frameshift mutations in the CNTNAP1 gene (602346.0001-602346.0003) in 7 newborns from 4 consanguineous families with an axoglial form of lethal congenital contracture syndrome (LCCS7; 616286). The fetal phenotype was severe, leading to death within the first 2 months of life. Immunohistochemical analysis of muscle and nerve from affected individuals showed defects of myelinated axons similar to those in mice lacking the Caspr gene.
In 3 sibs, born of consanguineous parents from Qatar, with LCCS7, Lakhani et al. (2017) identified a homozygous frameshift mutation in the CNTNAP1 gene (602346.0011). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function. Loss of the CASPR protein, which is encoded by the CNTNAP1 gene, results in improper organization of axoglial junctions in nerves. The loss of these axoglial junctions results in swelling of neuronal axons, decreased nerve conduction, reduced motor function, and death. In addition, the loss of myelination also affects the central nervous system.
Congenital Hypomyelinating Neuropathy 3
In 2 sets of brothers from unrelated families with congenital hypomyelinating neuropathy-3 (CHN3; 618186), Vallat et al. (2016) identified compound heterozygous mutations in the CNTNAP1 gene (602346.0004-602346.0007). These families were later reported by Hengel et al. (2017) and Nizon et al. (2017). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
By whole-exome sequencing, Mehta et al. (2017) identified a homozygous missense mutation in the CNTNAP1 gene (R388P; 602346.0008) in a patient with lethal CHN3. In vitro functional studies of the variant were not performed.
In 7 patients, including 2 sibs, with CHN3, Low et al. (2018) identified homozygous or compound heterozygous mutations in the CNTNAP1 gene (see, e.g., 602346.0009 and 602346.0010). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The mutations included 3 missense, 4 nonsense, 1 frameshift, and 1 splice site. All of the missense mutations occurred at conserved structural or functional domains and were predicted to adversely affect protein function according to ACMG guidelines, consistent with a loss of function. In vitro functional studies of the variants and studies of patient cells were not performed.
Bhat et al. (2001) found that Ncp1 -/- mice were born at the expected mendelian ratio and appeared normal at birth. However, Ncp1 -/- mice were slow to gain weight and showed progressive neurologic defects that reached maximal severity in the third postnatal week. Defects included hypomotility, tremor, wide-based gait, and generalized motor paresis. Light microscopic examination revealed no obvious abnormalities in organization or extent of myelination in Ncp1 -/- mice. However, immunofluorescence analysis of Ncp1 -/- sciatic nerve revealed mislocalization of the paranodal junction proteins contactin and neurofascin (NFASC; 609145) and abnormally overlapping domains of sodium and potassium channels. These defects were accompanied by reduced nerve conduction velocities. Electron microscopic analysis revealed loss of contact between glial cell membranes and axons at paranodal junctions in the central nervous system, but not in the peripheral nervous system.
By whole-exome sequencing in 2 sibs from a consanguineous family (K182) with distal lethal arthrogryposis multiplex congenita (LCCS7; 616286), Laquerriere et al. (2014) identified a homozygous 1-bp insertion (c.3009_3010insT, NM_003632) in exon 19 of the CNTNAP1 gene, leading to a frameshift (Phe1003fs). The parents were heterozygous for the mutation, which was not found in the Exome Variant Server or the dbSNP (build 138) databases. By whole-exome sequencing in an additional patient (K199) with lethal arthrogryposis multiplex congenita for whom parental DNA was unavailable, Laquerriere et al. (2014) identified the same 1-bp insertion.
By whole-exome sequencing in a male infant (B207) with distal lethal arthrogryposis multiplex congenita (LCCS7; 616286), for whom parental DNA was unavailable, Laquerriere et al. (2014) identified a homozygous 4-bp deletion involving the intron 18/exon 19 boundary (c.2993-2_2994del, NM_003632) of the CNTNAP1 gene, leading to a frameshift and premature termination (Ile999TrpfsTer5). Melki (2015) stated that the 4 deleted nucleotides were GATA. The mutation was not found in the Exome Variant Server or the dbSNP (build 138) databases.
By whole-exome sequencing in 3 sibs from a consanguineous family (A641) with distal lethal arthrogryposis multiplex congenita (LCCS7; 616286), Laquerriere et al. (2014) identified a homozygous 2-bp deletion (c.2901_2902del, NM_003632) in exon 18 of the CNTNAP1 gene, resulting in a frameshift and premature termination (Pro967ProfsTer12). Melki (2015) stated that the 2 deleted nucleotides were CT. The parents were heterozygous for the mutation, which had a minor allele frequency (0.00016) in the Exome Variant Server database (ESP6500SI-V2).
In 2 brothers of northern Irish descent with congenital hypomyelinating neuropathy-3 (CHN3; 618186), Vallat et al. (2016) and Hengel et al. (2017) identified compound heterozygous mutations in the CNTNAP1 gene: a c.2011C-T transition (c.2011C-T, NM_003632.2), resulting in a gln671-to-ter (Q671X) substitution, and a c.2290C-T transition, resulting in an arg764-to-cys (R764C; 602346.0005) substitution at a highly conserved residue. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The R764C variant was not found in the 1000 Genomes Project, Exome Sequencing Project, or ExAC databases. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
For discussion of the c.2290C-T transition (c.2290C-T, NM_003632.2) in the CNTNAP1 gene, resulting in an arg764-to-cys (R764C) substitution, that was found in compound heterozygous state in 2 brothers with congenital hypomyelinating neuropathy-3 (CHN3; 618186) by Vallat et al. (2016) and Hengel et al. (2017), see 602346.0004.
In 2 brothers of French descent with congenital hypomyelinating neuropathy-3 (CHN3; 618186), Vallat et al. (2016) and Nizon et al. (2017) identified compound heterozygous mutations in the CNTNAP1 gene: a c.967C-T transition (c.967C-T, NM_003632.2), resulting in a cys323-to-arg (C323R) substitution at a highly conserved residue predicted to be involved in a disulfide bond, and a c.1869G-A transition, resulting in a trp623-to-ter (W623X; 602346.0007) substitution. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The C323R variant was not found in the 1000 Genomes Project or Exome Variant Server databases, but was found twice in the ExAC database (2 in 120,018 alleles). Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
For discussion of the c.1869G-A transition (c.1869G-A, NM_003632.2) in the CNTNAP1 gene, resulting in trp623-to-ter (W623X), that was found in compound heterozygous state in 2 brothers with congenital hypomyelinating neuropathy-3 (CHN3; 618186) by Vallat et al. (2016) and Nizon et al. (2017), see 602346.0006.
In a male infant, born of unrelated parents, with lethal congenital hypomyelinating neuropathy-3 (CHN3; 618186), Mehta et al. (2017) identified a homozygous c.1163G-C transversion (chr17.40,839,856G-C) in the CNTNAP1 gene, resulting in an arg388-to-pro (R388P) substitution at a highly conserved residue. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was found once in the ExAC database (1 in 121,368 alleles). Functional studies of the variant and studies of patient cells were not performed, but molecular modeling suggesting that the mutation would destabilize the protein and interfere with normal functioning.
In 2 brothers (patients 2 and 3) with congenital hypomyelinating neuropathy-3 (CHN3; 618186), Low et al. (2018) identified compound heterozygous mutations in the CNTNAP1 gene: a c.635T-C transition (c.635T-C, NM_003632.2), resulting in a leu212-to-pro (L212P) substitution at a conserved residue, and a c.1677G-A transition, resulting in a trp559-to-ter (W559X; 602346.0010) substitution. The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variants and studies of patient cells were not performed, but the mutations were predicted to result in a loss of function.
For discussion of the c.1677G-A transition (c.1677G-A, NM_003632.2) in the CNTNAP1 gene, resulting in a trp559-to-ter (W559X) substitution, that was found in compound heterozygous state in 2 brothers with congenital hypomyelinating neuropathy-3 (CHN3; 618186) by Low et al. (2018), see 602346.0009.
In 3 sibs, born of consanguineous parents from Qatar, with lethal congenital contracture syndrome-7 (LCCS7; 616286), Lakhani et al. (2017) identified a homozygous 1-bp deletion (c.1561dupC, NM_003632.2) in the CNTNAP1 gene, resulting in a frameshift and premature termination (Leu521ProfsTer12). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the mutation was predicted to result in nonsense-mediated mRNA decay and a complete loss of function.
Bhat, M. A., Rios, J. C., Lu, Y., Garcia-Fresco, G. P., Ching, W., Martin, M. S., Li, J., Einheber, S., Chesler, M., Rosenbluth, J., Salzer, J. L., Bellen, H. J. Axon-glia interactions and the domain organization of myelinated axons requires neurexin IV/Caspr/paranodin. Neuron 30: 369-383, 2001. [PubMed: 11395000] [Full Text: https://doi.org/10.1016/s0896-6273(01)00294-x]
Faivre-Sarrailh, C., Gauthier, F., Denisendko-Nehrbass, N., Le Bivic, A., Rougon, G., Girault, J. A. The glycosylphosphatidyl inositol-anchored adhesion molecule F3/Contactin is required for surface transport of paranodin/contactin-associated protein (Caspr). J. Cell. Biol. 149: 491-502, 2000. [PubMed: 10769038] [Full Text: https://doi.org/10.1083/jcb.149.2.491]
Hengel, H., Magee, A., Mahanjah, M., Vallat, J.-M., Ouvrier, R., Abu-Rashid, M., Mahamid, J., Schule, R., Schulze, M., Krageloh-Mann, I., Bauer, P., Zuchner, S., Sharkia, R., Schols, L. CNTNAP1 mutations cause CNS hypomyelination and neuropathy with or without arthrogryposis. Neurol. Genet. 3: e144, 2017. Note: Electronic Article. [PubMed: 28374019] [Full Text: https://doi.org/10.1212/NXG.0000000000000144]
Lakhani, S., Doan, R., Almureikhi, M., Partlow, J. N., Al Saffar, M., Elsaid, M. F., Alaaraj, N., Barkovich, A. J., Walsh, C. A., Ben-Omran, T. Identification of a novel CNTNAP1 mutation causing arthrogryposis multiplex congenita with cerebral and cerebellar atrophy. Europ. J. Med. Genet. 60: 245-249, 2017. [PubMed: 28254648] [Full Text: https://doi.org/10.1016/j.ejmg.2017.02.006]
Laquerriere, A., Maluenda, J., Camus, A., Fontenas, L., Dieterich, K., Nolent, F., Zhou, J., Monnier, N., Latour, P., Gentil, D., Heron, D., Desguerres, I., and 48 others. Mutations in CNTNAP1 and ADCY6 are responsible for severe arthrogryposis multiplex congenita with axoglial defects. Hum. Molec. Genet. 23: 2279-2289, 2014. [PubMed: 24319099] [Full Text: https://doi.org/10.1093/hmg/ddt618]
Low, K. J., Stals, K., Caswell, R., Wakeling, M., Clayton-Smith, J., Donaldson, A., Foulds, N., Norman, A., Splitt, M., Urankar, K., Vijayakumar, K., Majumdar, A., DDD Study, Ellard, S., Smithson, S. F. Phenotype of CNTNAP1: a study of patients demonstrating a specific severe congenital hypomyelinating neuropathy with survival beyond infancy. Europ. J. Hum. Genet. 26: 796-807, 2018. [PubMed: 29511323] [Full Text: https://doi.org/10.1038/s41431-018-0110-x]
Mehta, P., Kuspert, M., Bale, T., Brownstein, C. A., Towne, M. C., De Girolami, U., Shi, J., Beggs, A. H., Darras, B. T., Wegner, M., Piao, X., Agrawal, P. B. Novel mutation in CNTNAP1 results in congenital hypomyelinating neuropathy. Muscle Nerve 55: 761-765, 2017. [PubMed: 27668699] [Full Text: https://doi.org/10.1002/mus.25416]
Melki, J. Personal Communication. Paris, France 4/9/2015.
Nizon, M., Cogne, B., Vallat, J.-M., Joubert, M., Liet, J.-M., Simon, L., Vincent, M., Kury, S., Boisseau, P., Schmitt, S., Mercier, S., Beneteau, C., Larrose, C., Coste, M., Latypova, X., Pereon, Y., Mussini, J.-M., Bezieau, S., Isidor, B. Two novel variants in CNTNAP1 in two siblings presenting with congenital hypotonia and hypomyelinating neuropathy. Europ. J. Hum. Genet. 25: 150-152, 2017. [PubMed: 27782105] [Full Text: https://doi.org/10.1038/ejhg.2016.142]
Peles, E., Nativ, M., Lustig, M., Grumet, M., Schilling, J., Martinez, R., Plowman, G. D., Schlessinger, J. Identification of a novel contactin-associated transmembrane receptor with multiple domains implicated in protein-protein interactions. EMBO J. 16: 978-988, 1997. [PubMed: 9118959] [Full Text: https://doi.org/10.1093/emboj/16.5.978]
Rios, J. C., Melendez-Vasquez, C. V., Einheber, S., Lustig, M., Grumet, M., Hemperly, J., Peles, E., Salzer, J. L. Contactin-associated protein (Caspr) and contactin form a complex that is targeted to the paranodal junctions during myelination. J. Neurosci. 20: 8354-8364, 2000. [PubMed: 11069942] [Full Text: https://doi.org/10.1523/JNEUROSCI.20-22-08354.2000]
Vallat, J.-M., Nizon, M., Magee, A., Isidor, B., Magy, L., Pereon, Y., Richard, L., Ouvrier, R., Cogne, B., Devaux, J., Zuchner, S., Mathis, S. Contactin-associated protein 1 (CNTNAP1) mutations induce characteristic lesions of the paranodal region. J. Neuropath. Exp. Neurol. 75: 1155-1159, 2016. [PubMed: 27818385] [Full Text: https://doi.org/10.1093/jnen/nlw093]