title: Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain.
abstract: The neuromuscular junction (NMJ) consists of a tripartite synapse with a presynaptic nerve terminal, Schwann cells that ensheathe the terminal bouton, and a highly specialized postsynaptic membrane. Synaptic structural integrity is crucial for efficient signal transmission. Congenital myasthenic syndromes (CMSs) are a heterogeneous group of inherited disorders that result from impaired neuromuscular transmission, caused by mutations in genes encoding proteins that are involved in synaptic transmission and in forming and maintaining the structural integrity of NMJs. To identify further causes of CMSs, we performed whole-exome sequencing (WES) in families without an identified mutation in known CMS-associated genes. In two families affected by a previously undefined CMS, we identified homozygous loss-of-function mutations in COL13A1, which encodes the alpha chain of an atypical non-fibrillar collagen with a single transmembrane domain. COL13A1 localized to the human muscle motor endplate. Using CRISPR-Cas9 genome editing, modeling of the COL13A1 c.1171delG (p.Leu392Sfs(∗)71) frameshift mutation in the C2C12 cell line reduced acetylcholine receptor (AChR) clustering during myotube differentiation. This highlights the crucial role of collagen XIII in the formation and maintenance of the NMJ. Our results therefore delineate a myasthenic disorder that is caused by loss-of-function mutations in COL13A1, encoding a protein involved in organization of the NMJ, and emphasize the importance of appropriate symptomatic treatment for these individuals.
authors.affiliation: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Clare V
authors.initials: CV
authors.lastname: Logan
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Judith
authors.initials: J
authors.lastname: Cossins
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Pedro M
authors.initials: PM
authors.lastname: Rodríguez Cruz
authors.affiliation: Section of Genetics, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: David A
authors.initials: DA
authors.lastname: Parry
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Susan
authors.initials: S
authors.lastname: Maxwell
authors.affiliation: Neuroimmunology Group, Division of Neuroscience, School for Mental Health and Neuroscience, Maastricht University, PO box 616, 6200 MD Maastricht, the Netherlands.
authors.forename: Pilar
authors.initials: P
authors.lastname: Martínez-Martínez
authors.affiliation: MRC Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Joey
authors.initials: J
authors.lastname: Riepsaame
authors.affiliation: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Zakia A
authors.initials: ZA
authors.lastname: Abdelhamed
authors.affiliation: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Alice V R
authors.initials: AV
authors.lastname: Lake
authors.affiliation: Department of Paediatric Neurology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Maria
authors.initials: M
authors.lastname: Moran
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Robb
authors.affiliation: Department of Paediatric Neurology, Nottingham City Hospital, Nottingham University Hospitals NHS Trust, Hucknall Road, Nottingham NG5 1PB, UK.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Chow
authors.affiliation: Dubowitz Neuromuscular Centre, Institute of Child Health and Great Ormond Street Hospital, 30 Guilford Street, London WC1N 1EH, UK.
authors.forename: Caroline
authors.initials: C
authors.lastname: Sewry
authors.affiliation: Section of Translational Anaesthesia and Surgical Sciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Philip M
authors.initials: PM
authors.lastname: Hopkins
authors.affiliation: Section of Genetics, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK.
authors.forename: Eamonn
authors.initials: E
authors.lastname: Sheridan
authors.affiliation: Department of Paediatric Neurology, John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 9DU, UK.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Jayawant
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK; Department of Clinical Neurology, John Radcliffe Hospital, Oxford Radcliffe Hospitals NHS Trust, Oxford OX3 9DU, UK.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Palace
authors.affiliation: Section of Ophthalmology & Neurosciences, Leeds Institute of Biomedical and Clinical Sciences, University of Leeds, Leeds LS9 7TF, UK. Electronic address: c.johnson@leeds.ac.uk.
authors.forename: Colin A
authors.initials: CA
authors.lastname: Johnson
authors.affiliation: Neurosciences Group, Nuffield Department of Clinical Neurosciences, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK. Electronic address: david.beeson@ndcn.ox.ac.uk.
authors.forename: David
authors.initials: D
authors.lastname: Beeson
mesh_terms: D000328:Adult; D000818:Animals; D002460:Cell Line; D002675:Child, Preschool; D064112:Clustered Regularly Interspaced Short Palindromic Repeats; D024181:Collagen Type XIII / Q000235:genetics* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D059472:Exome; D005260:Female; D015870:Gene Expression; D059014:High-Throughput Nucleotide Sequencing; D006720:Homozygote; D006801:Humans; D008297:Male; D051379:Mice; D009154:Mutation; D020294:Myasthenic Syndromes, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D032446:Myoblasts / Q000378:metabolism* / Q000473:pathology; D009469:Neuromuscular Junction / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D010375:Pedigree; D011950:Receptors, Cholinergic / Q000235:genetics / Q000378:metabolism; D013569:Synapses / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D009435:Synaptic Transmission
chemical_list: D024181:Collagen Type XIII; D011950:Receptors, Cholinergic; D004720:Endonucleases