Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy Alison G. Compton,

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Mutations in Contactin-1, a Neural Adhesion and Neuromuscular Junction Protein, Cause a Familial Form of Lethal Congenital Myopathy Alison G. Compton, Douglas E. Albrecht, Jane T. Seto, Sandra T. Cooper, Biljana Ilkovski, Kristi J. Jones, Daniel Challis, David Mowat, Barbara Ranscht, Melanie Bahlo, Stanley C. Froehner, Kathryn N. North The American Journal of Human Genetics Volume 83, Issue 6, Pages 714-724 (December 2008) DOI: 10.1016/j.ajhg.2008.10.022 Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 1 Family Pedigree and Skeletal Muscle Pathology (A) Pedigree indicating family members studied with linkage analysis (initial mapping performed on individuals marked with an asterisk) and genotype. Filled symbols indicate affected individuals and half-filled symbols indicate carrier status (assessed by genotyping). All empty symbols indicate family members for which samples were unavailable for testing. (B and B′) Electron micrograph of skeletal muscle from affected individual V:7. Fibers contained foci of sarcomeric disruption and z-line streaming. (B) shows a micrograph magnification at 4500×, and (B′) shows a micrograph magnification at 10,000×. (C–H) Immunohistochemistry of muscle sections from patient V:7 (C, D, E, F, G, and H) and age-matched control (E′, F′, and G′) for members of the dystrophin-associated protein complex. Shown are (C) α-dystroglycan, (D) α1-syntrophin, (E and E′) β1-syntrophin, (F and F′) α-dystrobrevin-2, (G and G′) β2-syntrophin, and (H) slow myosin. All members of the dystrophin-associated protein complex were expressed normally except select members of the syntrophin-α-dystrobrevin subcomplex. All affected family members showed an absence of sarcolemmal membrane expression for β2-syntrophin (which is normally expressed at the sarcolemma of slow fibers (G′ marked with an asterisk in the age-matched control) and α-dystrobrevin. Slow myosin shows the presence of slow fibers in the patient biopsy. Scale bars represent 40 μm. Biopsies were taken from quadriceps at developmental age 35 weeks' gestation. The American Journal of Human Genetics 2008 83, 714-724DOI: (10.1016/j.ajhg.2008.10.022) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 2 Linkage and Mutation Analysis (A) Parametric multipoint linkage analysis results of the chromosome 12 disease locus in this Egyptian family. An idiotype of chromosome 12 reports the position of the locus within the flanking recombination markers D12S1688 and D12S1663. Electropherograms show the mutation containing region in control, unaffected parent and affected infant. The duplication of a thymine between position 871 and 872 is indicated by an arrow. Both the control and the affected normal protein sequences are shown below the respective electropherogram. A schematic of the contactin-1 protein shows the position of the amino acid mutation, S291fsX296, in relation to the full-length 1018 amino acid protein (gray ovals represent Ig-like domains, black boxes indicate FNIII domains, and the C-terminal arrow indicates the GPI-anchor). (B) The nucleotides and amino acids flanking the insertion (gray shaded) are highly conserved in different species (human contactin-1 nucleotides 848–894, amino acids 262–314). Orthologs in Homo sapiens, Pongo troglodytes, Pongo pygmaeus, Mus musculus, Rattus norvegicus, Bos taurus, Gallus gallus, Xenopus laevis, and Danio rerio are shown. Stars indicate conserved residues. The American Journal of Human Genetics 2008 83, 714-724DOI: (10.1016/j.ajhg.2008.10.022) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 3 Contactin-1 Localization at the NMJ in Both Human and Mouse Skeletal Muscle Confocal immunofluorescence in normal human and mouse quadriceps muscle showing overlap between contactin-1 (CNTN) and α-bungarotoxin (Txn) used to highlight the acetylcholine receptors of the NMJ. Arrows are used to indicate an example of this staining. The American Journal of Human Genetics 2008 83, 714-724DOI: (10.1016/j.ajhg.2008.10.022) Copyright © 2008 The American Society of Human Genetics Terms and Conditions

Figure 4 Contactin-1 Is Mislocalized to the Sarcolemmal Membrane in the Absence of Glycosylated α-Dystroglycan Confocal immunofluorescence of skeletal muscle biopsies from secondary α-dystroglycanopathy patients (mutations in FKRP [B and C] and POMTGnT1 [D]), (E) denervation disorder (SMA [MIM 253300]), and (F) Duchenne muscular dystrophy (DMD) as compared to (A) control muscle with polyclonal anti-contactin-1 antibodies. Contactin-1 expression is mislocalized to the sarcolemmal membrane in response to loss of glycosylated α-dystroglycan (indicated with arrows in [B], [C], and [D]) but not in response to generalized dystrophic changes or denervation. In the control (A), contactin-1 is retained at the NMJ (indicated with arrow). The control shown is not age matched for all biopsies because NMJs are not present in all human biopsies as a result of sampling. The American Journal of Human Genetics 2008 83, 714-724DOI: (10.1016/j.ajhg.2008.10.022) Copyright © 2008 The American Society of Human Genetics Terms and Conditions