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Biomolecules
Special Issues
Pathophysiological Insights into Congenital Myasthenic Syndromes
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Pathophysiological Insights into Congenital Myasthenic Syndromes

A Special Issue of Biomolecules (ISSN 2218-273X) belonging to the section "Molecular Medicine".

Deadline for manuscript submissions: 31 October 2026 | Viewed by 4201

Editors

Dr. Xin-Ming Shen

E-Mail Website
Guest Editor
Department of Neurology, Mayo Clinic, Mayo Clinic College of Medicine, Rochester, MN, USA
Interests: neuromuscular transmission; neuromuscular diseases; synapse biology; receptor and ion channel kinetics; enzyme kinetics; protein interaction; protein structure–function relationships
Dr. Kinji Ohno

E-Mail Website
Guest Editor
Division of Neurogenetics, Center for Neurological Diseases and Cancer, Nagoya University Graduate School of Medicine, Nagoya, Aichi, Japan
Interests: neuromuscular junction; mitochondrial homeostasis; RNA metabolism; data science and machine learning; parkinson’s disease; gut microbiota; electromagnetic field
Dr. Duygu Selcen

E-Mail Website
Guest Editor
Department of Neurology, Mayo Clinic, Mayo Clinic College of Medicine, Rochester, MN, USA
Interests: neuromuscular junction; congenital myasthenic syndrome; neuromuscular diseases; muscle pathology

Special Issue Information

Dear Colleagues,

Congenital myasthenic syndromes (CMSs) are a diverse group of inherited neuromuscular disorders caused by impaired neuromuscular transmission, resulting in fatigable muscle weakness. Advances in genetics, molecular biology, and neuropathology have greatly enhanced our understanding of CMSs, uncovering distinct pathogenic mechanisms involving presynaptic, synaptic, and postsynaptic defects. However, significant challenges remain in achieving timely and accurate diagnosis, establishing precise genotype–phenotype correlations, and identifying novel therapeutic targets.

This Special Issue of Biomolecules, entitled “Pathophysiological Insights into Congenital Myasthenic Syndromes”, will provide a platform for original research articles and comprehensive reviews that will advance our knowledge of the molecular and cellular basis of CMSs. We welcome the inclusion of research based on case descriptions of CMSs of known or undefined etiology, including cases occurring in combination with other disorders, as they provide valuable insights into novel phenotype–genotype relationships, mechanistic understanding, translational applications, and potential treatment improvements, thereby further enriching the manuscript. Studies addressing structural, functional, or biochemical alterations to neuromuscular junction components, novel gene variants and their pathogenicity, disease modeling, and the mechanisms behind synaptic dysfunction are highly encouraged.

By bridging molecular insights and clinical perspectives, this Special Issue will enhance our understanding of CMS pathophysiology and promote the development of improved diagnostic approaches and targeted therapeutic strategies.

We look forward to receiving your contributions to this Special Issue.

Dr. Xin-Ming Shen
Dr. Kinji Ohno
Dr. Duygu Selcen
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 250 words) can be sent to the Editorial Office for assessment.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-anonymized peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomolecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • neuromuscular junction
  • neurotransmission
  • developmental biology
  • myasthenia
  • congenital myasthenic syndrome
  • human genetics
  • variant
  • mutation
  • animal model

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Published Papers (3 papers)

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Research

16 pages, 2426 KB  
Article
Congenital Myasthenic Syndrome in Doberman Pinscher Dogs Is Associated with a Homozygous Missense Variant in AGRN
by G. Diane Shelton, Joan R. Coates, Janet E. Steiss, Ling T. Guo, Simon R. Platt, Katie M. Minor, Steven G. Friedenberg, Jonah N. Cullen, Garrett Bullock, Elizabeth A. Hansen, Martin L. Katz and Gary S. Johnson
Biomolecules 2026, 16(8), 1099; https://doi.org/10.3390/biom16081099 - 28 Jul 2026
Viewed by 2599
Abstract
Hereditary neuromuscular disorders in dogs can be difficult to classify since variants in different genes can result in similar clinical signs or variable phenotypes can be associated with the same DNA sequence variant. A disorder known for many years as Dancing Doberman Disease, [...] Read more.
Hereditary neuromuscular disorders in dogs can be difficult to classify since variants in different genes can result in similar clinical signs or variable phenotypes can be associated with the same DNA sequence variant. A disorder known for many years as Dancing Doberman Disease, suspected to be neuropathy or neuromyopathy, is characterized by repeated lifting and shifting of the pelvic limbs while standing and frequent sitting. More recently, Doberman Pinschers have been identified with a different and more severe phenotype characterized by a crouched stance and bunny hopping gait in the pelvic limbs that is termed duck walking. Dogs with both phenotypes show pelvic limb weakness, muscle atrophy, and fatigue, and clinical signs can progress to involve the thoracic limbs. These distinct phenotypes were evaluated clinically, histologically, and by whole-genome sequencing and genotyping a large cohort of affected and unaffected Doberman Pinschers. The same homozygous missense variant in AGRN (Dog 10K Boxer Tasha chr5:56,346,611,G>A; p.R1710H, XP 038377340.1) was associated with both disorders. AGRN encodes Agrin, an essential synaptic protein, that mediates clustering of acetylcholine receptors on the post-synaptic membrane at the neuromuscular junction. Variants in AGRN are associated with a congenital myasthenic syndrome (CMS) in humans. This is the first report of a CMS in dogs associated with an AGRN variant and expands the spectrum of known CMS genetic risk factors in this species. This study also highlights the importance of whole-genome sequencing (WGS) to accurately classify neuromuscular diseases as forms of CMS, which is not possible based on clinical presentation alone. Full article
(This article belongs to the Special Issue Pathophysiological Insights into Congenital Myasthenic Syndromes)
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23 pages, 11535 KB  
Article
Hexosamine Pathway Disruption by GFPT1 Loss Drives Coordinated Defects in Glycosylation, Autophagy, and Trafficking
by Stephen H. Holland, Ricardo Carmona-Martinez, Andreas Hentschel, Alexa Derksen, Kaela O’Connor, Daniel O’Neil, Kelly Ho, Stephen D. Baird, Andreas Roos, Sally Spendiff and Hanns Lochmüller
Biomolecules 2026, 16(7), 966; https://doi.org/10.3390/biom16070966 - 30 Jun 2026
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Abstract
Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction [...] Read more.
Glutamine-Fructose-6-Phosphate Transaminase 1 (GFPT1), the rate-limiting enzyme of the hexosamine biosynthetic pathway (HBP), provides the UDP-N-acetylglucosamine (UDP-GlcNAc) required for protein glycosylation. Biallelic mutations in GFPT1 cause congenital myasthenic syndromes (GFPT1-CMS), yet the molecular mechanisms linking impaired glycosylation to skeletal muscle dysfunction remain incompletely understood. Here, we combine cellular models of inducible Gfpt1 knockdown and a skeletal muscle-specific Gfpt1 knockout mouse (Gfpt1Tm1d/Tm1d) with whole-cell proteomics, immunoblot studies and secretomics to define glycosylation-dependent defects in intracellular trafficking, ER stress signaling and autophagy. Global proteomic profiling of Gfpt1-deficient myoblasts revealed marked downregulation of protein trafficking pathways and impaired secretion of key muscle cargo proteins, including serglycin (Srgn). Loss of GFPT1 reduced both high-molecular-weight glycosylated serglycin and its core protein, accompanied by intracellular retention and decreased secretion. These trafficking defects coincide with robust activation of the unfolded protein response (UPR), evidenced by increased Xbp1 expression and accumulation of spliced Xbp1s across pharmacologic, cellular, and mouse models of GFPT1 deficiency. Converging evidence from proteomics, immunoblotting, and immunofluorescence demonstrated impaired autophagy, including increased LC3-II accumulation, elevated p62/Sqstm1 levels, and enhanced p62-positive puncta in both Gfpt1-deficient C2C12 myoblasts and skeletal muscle. Soluble/insoluble fractionation further confirmed p62 accumulation, indicating defective autophagic flux and buildup of aggregated cargo. Together, these findings identify a glycosylation-dependent failure in protein trafficking that triggers ER stress, UPR activation, and autophagy impairment in Gfpt1-deficient skeletal muscle. This mechanistic cascade provides a unifying explanation for muscle pathology in GFPT1-CMS and suggests that restoring glycosylation or improving proteostasis may represent viable therapeutic approaches. Full article
(This article belongs to the Special Issue Pathophysiological Insights into Congenital Myasthenic Syndromes)
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14 pages, 2328 KB  
Article
Mouse Model of Fast-Channel Genetic Myasthenic Syndrome Carrying Chrne p.P141L Mutation
by Richard G. Webster, Susan Maxwell and Yin Y. Dong
Biomolecules 2026, 16(7), 931; https://doi.org/10.3390/biom16070931 - 23 Jun 2026
Viewed by 579
Abstract
Fast-channel genetic myasthenic syndromes (FCGMSs) are caused by genetic variants in muscle nicotinic acetylcholine receptor (AChR) subunits that reduce channel open times and impair neuromuscular transmission. Among these, the CHRNE p.P141L variant (εP141L) is associated with particularly severe disease. Here, we characterized a [...] Read more.
Fast-channel genetic myasthenic syndromes (FCGMSs) are caused by genetic variants in muscle nicotinic acetylcholine receptor (AChR) subunits that reduce channel open times and impair neuromuscular transmission. Among these, the CHRNE p.P141L variant (εP141L) is associated with particularly severe disease. Here, we characterized a knock-in mouse model harboring the homologous p.P141L variant in Chrne (εP141L)—C57BL/6J-Chrneem1H/H made by the MRC GEMM program. Homozygous mutant mice fail to thrive, with early lethality (median survival of 16 days), closely recapitulating the severity observed in patients. Despite a preserved neuromuscular junction (NMJ) morphology and robust AChR expression, electrophysiological analyses revealed marked reductions in miniature and evoked endplate potential amplitudes and areas, accompanied by prolonged depolarization kinetics (contrary to expectations for AChR with reduced open times) and increased quantal content, indicative of impaired post-synaptic function with compensatory pre-synaptic adaptation. Notably, disease severity exceeded that of Chrne null mice, likely through competition with more functional g-subunit-containing fetal AChRs. Consistent with this, crossing εP141L mice with CHRNG-expressing mice provided little survival benefit. These findings demonstrate that dysfunctional AChR incorporation is more deleterious than receptor absence and highlight the critical role of subunit composition in sustaining neuromuscular transmission. Pharmacological enhancement of pre-synaptic release with 3,4-diaminopyridine partially improved synaptic parameters. In addition, the AChR-positive allosteric modulator DC-98 modestly improved neurotransmission. Thus, this mouse model provides a faithful platform for mechanistic studies and therapeutic development in FCGMS. Full article
(This article belongs to the Special Issue Pathophysiological Insights into Congenital Myasthenic Syndromes)
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