Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain

Clare V Logan, Judith Cossins, Pedro M Rodríguez Cruz, David A Parry, Susan Maxwell, Pilar Martínez-Martínez, Joey Riepsaame, Zakia A Abdelhamed, Alice V R Lake, Maria Moran, Stephanie Robb, Gabriel Chow, Caroline Sewry, Philip M Hopkins, Eamonn Sheridan, Sandeep Jayawant, Jacqueline Palace, Colin A Johnson, David Beeson

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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.

Original languageEnglish
Pages (from-to)878-85
Number of pages8
JournalAmerican Journal of Human Genetics
Volume97
Issue number6
DOIs
Publication statusPublished - 3 Dec 2015

Keywords

  • Adult
  • Animals
  • Cell Line
  • Child, Preschool
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Collagen Type XIII
  • Endonucleases
  • Exome
  • Female
  • Gene Expression
  • High-Throughput Nucleotide Sequencing
  • Homozygote
  • Humans
  • Male
  • Mice
  • Mutation
  • Myasthenic Syndromes, Congenital
  • Myoblasts
  • Neuromuscular Junction
  • Pedigree
  • Receptors, Cholinergic
  • Synapses
  • Synaptic Transmission

Cite this

Logan, C. V., Cossins, J., Rodríguez Cruz, P. M., Parry, D. A., Maxwell, S., Martínez-Martínez, P., Riepsaame, J., Abdelhamed, Z. A., Lake, A. V. R., Moran, M., Robb, S., Chow, G., Sewry, C., Hopkins, P. M., Sheridan, E., Jayawant, S., Palace, J., Johnson, C. A., & Beeson, D. (2015). Congenital Myasthenic Syndrome Type 19 Is Caused by Mutations in COL13A1, Encoding the Atypical Non-fibrillar Collagen Type XIII α1 Chain. American Journal of Human Genetics, 97(6), 878-85. https://doi.org/10.1016/j.ajhg.2015.10.017