title: Mutations in contactin-1, a neural adhesion and neuromuscular junction protein, cause a familial form of lethal congenital myopathy.
abstract: We have previously reported a group of patients with congenital onset weakness associated with a deficiency of members of the syntrophin-alpha-dystrobrevin subcomplex and have demonstrated that loss of syntrophin and dystrobrevin from the sarcolemma of skeletal muscle can also be associated with denervation. Here, we have further studied four individuals from a consanguineous Egyptian family with a lethal congenital myopathy inherited in an autosomal-recessive fashion and characterized by a secondary loss of beta2-syntrophin and alpha-dystrobrevin from the muscle sarcolemma, central nervous system involvement, and fetal akinesia. We performed homozygosity mapping and candidate gene analysis and identified a mutation that segregates with disease within CNTN1, the gene encoding for the neural immunoglobulin family adhesion molecule, contactin-1. Contactin-1 transcripts were markedly decreased on gene-expression arrays of muscle from affected family members compared to controls. We demonstrate that contactin-1 is expressed at the neuromuscular junction (NMJ) in mice and man in addition to the previously documented expression in the central and peripheral nervous system. In patients with secondary dystroglycanopathies, we show that contactin-1 is abnormally localized to the sarcolemma instead of exclusively at the NMJ. The cntn1 null mouse presents with ataxia, progressive muscle weakness, and postnatal lethality, similar to the affected members in this family. We propose that loss of contactin-1 from the NMJ impairs communication or adhesion between nerve and muscle resulting in the severe myopathic phenotype. This disorder is part of the continuum in the clinical spectrum of congenital myopathies and congenital myasthenic syndromes.
authors.affiliation: Institute for Neuromuscular Research, The Children's Hospital at Westmead, NSW, Australia.
authors.forename: Alison G
authors.initials: AG
authors.lastname: Compton
authors.forename: Douglas E
authors.initials: DE
authors.lastname: Albrecht
authors.forename: Jane T
authors.initials: JT
authors.lastname: Seto
authors.forename: Sandra T
authors.initials: ST
authors.lastname: Cooper
authors.forename: Biljana
authors.initials: B
authors.lastname: Ilkovski
authors.forename: Kristi J
authors.initials: KJ
authors.lastname: Jones
authors.forename: Daniel
authors.initials: D
authors.lastname: Challis
authors.forename: David
authors.initials: D
authors.lastname: Mowat
authors.forename: Barbara
authors.initials: B
authors.lastname: Ranscht
authors.forename: Melanie
authors.initials: M
authors.lastname: Bahlo
authors.forename: Stanley C
authors.initials: SC
authors.lastname: Froehner
authors.forename: Kathryn N
authors.initials: KN
authors.lastname: North
mesh_terms: D000595:Amino Acid Sequence; D019943:Amino Acid Substitution; D001483:Base Sequence; D016022:Case-Control Studies; D015816:Cell Adhesion Molecules, Neuronal / Q000235:genetics*; D019457:Chromosome Breakage; D002874:Chromosome Mapping; D002881:Chromosomes, Human, Pair 12; D015331:Cohort Studies; D003241:Consanguinity; D017124:Conserved Sequence; D058967:Contactin 1; D058966:Contactins; D004252:DNA Mutational Analysis; D049029:Dystrophin-Associated Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D008040:Genetic Linkage; D005819:Genetic Markers; D006239:Haplotypes; D006720:Homozygote; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D008297:Male; D018895:Microsatellite Repeats; D008969:Molecular Sequence Data; D018482:Muscle, Skeletal / Q000737:chemistry / Q000378:metabolism / Q000473:pathology* / Q000648:ultrastructure; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism; D009469:Neuromuscular Junction / Q000235:genetics* / Q000378:metabolism; D010375:Pedigree; D012508:Sarcolemma / Q000378:metabolism; D012518:Sarcomeres / Q000473:pathology / Q000648:ultrastructure
chemical_list: C548669:CNTN1 protein, human; D015816:Cell Adhesion Molecules, Neuronal; C548670:Cntn1 protein, mouse; D058967:Contactin 1; D058966:Contactins; D049029:Dystrophin-Associated Proteins; D005819:Genetic Markers; C098885:dystrobrevin; C091824:syntrophin