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The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.

Publication ,  Journal Article
Cocanougher, BT; Liu, SW; Francescatto, L; Behura, A; Anneling, M; Jackson, DG; Deak, KL; Hornik, CD; ElMallah, MK; Pizoli, CE; Smith, EC ...
Published in: HGG Adv
July 18, 2024

Biallelic loss-of-function variants in the MUSK gene result in two allelic disorders: (1) congenital myasthenic syndrome (CMS; OMIM: 616325), a neuromuscular disorder that has a range of severity from severe neonatal-onset weakness to mild adult-onset weakness, and (2) fetal akinesia deformation sequence (OMIM: 208150), a form of pregnancy loss characterized by severe muscle weakness in the fetus. The MUSK gene codes for muscle-specific kinase (MuSK), a receptor tyrosine kinase involved in the development of the neuromuscular junction. Here, we report a case of neonatal-onset MUSK-related CMS in a patient harboring compound heterozygous deletions in the MUSK gene, including (1) a deletion of exons 2-3 leading to an in-frame MuSK protein lacking the immunoglobulin 1 (Ig1) domain and (2) a deletion of exons 7-11 leading to an out-of-frame, truncated MuSK protein. Individual domains of the MuSK protein have been elucidated structurally; however, a complete MuSK structure generated by machine learning algorithms has clear inaccuracies. We modify a predicted AlphaFold structure and integrate previously reported domain-specific structural data to suggest a MuSK protein that dimerizes in two locations (Ig1 and the transmembrane domain). We analyze known pathogenic variants in MUSK to discover domain-specific genotype-phenotype correlations; variants that lead to a loss of protein expression, disruption of the Ig1 domain, or Dok-7 binding are associated with the most severe phenotypes. A conceptual model is provided to explain the severe phenotypes seen in Ig1 variants and the poor response of our patient to pyridostigmine.

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Published In

HGG Adv

DOI

EISSN

2666-2477

Publication Date

July 18, 2024

Volume

5

Issue

3

Start / End Page

100288

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Receptors, Cholinergic
  • Receptor Protein-Tyrosine Kinases
  • Protein Domains
  • Myasthenic Syndromes, Congenital
  • Male
  • Infant, Newborn
  • Humans
  • Female
  • 3105 Genetics
 

Citation

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Cocanougher, B. T., Liu, S. W., Francescatto, L., Behura, A., Anneling, M., Jackson, D. G., … McDonald, M. T. (2024). The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt. HGG Adv, 5(3), 100288. https://doi.org/10.1016/j.xhgg.2024.100288
Cocanougher, Benjamin T., Samuel W. Liu, Ludmila Francescatto, Alexander Behura, Mariele Anneling, David G. Jackson, Kristen L. Deak, et al. “The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.HGG Adv 5, no. 3 (July 18, 2024): 100288. https://doi.org/10.1016/j.xhgg.2024.100288.
Cocanougher BT, Liu SW, Francescatto L, Behura A, Anneling M, Jackson DG, et al. The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt. HGG Adv. 2024 Jul 18;5(3):100288.
Cocanougher, Benjamin T., et al. “The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt.HGG Adv, vol. 5, no. 3, July 2024, p. 100288. Pubmed, doi:10.1016/j.xhgg.2024.100288.
Cocanougher BT, Liu SW, Francescatto L, Behura A, Anneling M, Jackson DG, Deak KL, Hornik CD, ElMallah MK, Pizoli CE, Smith EC, Tan KGQ, McDonald MT. The severity of MUSK pathogenic variants is predicted by the protein domain they disrupt. HGG Adv. 2024 Jul 18;5(3):100288.

Published In

HGG Adv

DOI

EISSN

2666-2477

Publication Date

July 18, 2024

Volume

5

Issue

3

Start / End Page

100288

Location

United States

Related Subject Headings

  • Severity of Illness Index
  • Receptors, Cholinergic
  • Receptor Protein-Tyrosine Kinases
  • Protein Domains
  • Myasthenic Syndromes, Congenital
  • Male
  • Infant, Newborn
  • Humans
  • Female
  • 3105 Genetics