Identification of mutations in the<i>MYO9A</i>gene in patients with congenital myasthenic syndrome

O’Connor, Emily; Töpf, Ana; Müller, Juliane S.; Cox, Dan; Evangelista, Teresinha; Colomer, J.; Schöser, Benedikt; Senderek, Jan; Hasselmann, Oswald; Yaramış, Ahmet; Laval, Steven H.; Lochmüller, Hanns

doi:10.1093/brain/aww130

Cited by 48 publications

(60 citation statements)

References 48 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Next generation sequencing methods in recent years facilitated discovery of mutations in other presynaptic proteins essential for neuromuscular transmission. These include synaptotagmin 2, SNAP25B (synaptosomal‐associated protein 25B), Munc13‐1, myosin 9A, the high‐affinity choline transporter, and the vesicular acetylcholine (ACh) transporter . Here, we describe the clinical features and molecular pathogenesis of another presynaptic CMS caused by a homozygous frameshift mutation in synaptobrevin 1 ( SYB1 , also known as VAMP1 ; OMIM: 185880).…”

Section: Introductionmentioning

confidence: 99%

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Shen

Scola

Lorenzoni

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

ObjectiveTo identify the molecular basis and elucidate the pathogenesis of a fatal congenital myasthenic syndrome.MethodsWe performed clinical electrophysiology studies, exome and Sanger sequencing, and analyzed functional consequences of the identified mutation.ResultsClinical electrophysiology studies of the patient revealed several‐fold potentiation of the evoked muscle action potential by high frequency nerve stimulation pointing to a presynaptic defect. Exome sequencing identified a homozygous c.340delA frameshift mutation in synaptobrevin 1 (SYB1), one of the three SNARE proteins essential for synaptic vesicle exocytosis. Analysis of both human spinal cord gray matter and normal human muscle revealed expression of the SYB1A and SYB1D isoforms, predicting expression of one or both isoforms in the motor nerve terminal. The identified mutation elongates the intravesicular C‐terminus of the A isoform from 5 to 71, and of the D isoform from 4 to 31 residues. Transfection of either mutant isoform into bovine chromaffin cells markedly reduces depolarization‐evoked exocytosis, and transfection of either mutant isoform into HEK cells significantly decreases expression of either mutant compared to wild type.InterpretationThe mutation is pathogenic because elongation of the intravesicular C‐terminus of the A and D isoforms increases the energy required to move their C‐terminus into the synaptic vesicle membrane, a key step for fusion of the synaptic vesicle with the presynaptic membrane, and because it is predicted to reduce expression of either isoform in the nerve terminal.

show abstract

Section: Introductionmentioning

confidence: 99%

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Shen

Scola

Lorenzoni

et al. 2017

Ann Clin Transl Neurol

View full text Add to dashboard Cite

show abstract

“…In zebrafish popdc3 morphants, many embryos displayed a curled tail phenotype, which has been described in mutants and morphants of genes involved in ciliopathies . Presently, the relation of the curled tail phenotype to muscular dystrophy remains unclear; however, several morphants of genes causing muscular dystrophy or congenital myasthenic syndrome also display a curled tail similar to the one observed in popdc3 morphants . In addition, we also observed embryos that displayed dystrophic changes in the tail musculature, which were probably caused by myofiber rupture.…”

Section: Discussionmentioning

confidence: 81%

“…30 Presently, the relation of the curled tail phenotype to muscular dystrophy remains unclear; however, several morphants of genes causing muscular dystrophy or congenital myasthenic syndrome also display a curled tail similar to the one observed in popdc3 morphants. [31][32][33][34] In addition, we also observed embryos that displayed dystrophic changes in the tail musculature, which were probably caused by myofiber rupture. Interestingly, myofiber rupture has been observed previously in the case of the zebrafish popdc1 S191F knockin mutant and in mutants and morphants of genes causing muscular dystrophy.…”

Section: Zebrafish Model Indicates Important Role Of Popdc3 For Musclmentioning

confidence: 88%

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Vissing

Johnson

Töpf

et al. 2019

Annals of Neurology

Self Cite

View full text Add to dashboard Cite

Objective The Popeye domain containing 3 (POPDC3) gene encodes a membrane protein involved in cyclic adenosine monophosphate (cAMP) signaling. Besides gastric cancer, no disease association has been described. We describe a new muscular dystrophy associated with this gene. Methods We screened 1,500 patients with unclassified limb girdle weakness or hyperCKemia for pathogenic POPDC3 variants. Five patients carrying POPDC3 variants were examined by muscle magnetic resonance imaging (MRI), muscle biopsy, and cardiac examination. We performed functional analyses in a zebrafish popdc3 knockdown model and heterologous expression of the mutant proteins in Xenopus laevis oocytes to measure TREK‐1 current. Results We identified homozygous POPDC3 missense variants (p.Leu155His, p.Leu217Phe, and p.Arg261Gln) in 5 patients from 3 ethnically distinct families. Variants affected highly conserved residues in the Popeye (p.Leu155 and p.Leu217) and carboxy‐terminal (p.Arg261) domains. The variants were almost absent from control populations. Probands’ muscle biopsies were dystrophic, and serum creatine kinase levels were 1,050 to 9,200U/l. Muscle weakness was proximal with adulthood onset in most patients and affected lower earlier than upper limbs. Muscle MRI revealed fat replacement of paraspinal and proximal leg muscles; cardiac investigations were unremarkable. Knockdown of popdc3 in zebrafish, using 2 different splice‐site blocking morpholinos, resulted in larvae with tail curling and dystrophic muscle features. All 3 mutants cloned in Xenopus oocytes caused an aberrant modulation of the mechano‐gated potassium channel, TREK‐1. Interpretation Our findings point to an important role of POPDC3 for skeletal muscle function and suggest that pathogenic variants in POPDC3 are responsible for a novel type of autosomal recessive limb girdle muscular dystrophy. ANN NEUROL 2019;86:832–843

show abstract

“…12 The family history included four previous children dying in the first year of life due to respiratory failure, feeding difficulties and hypotonia. The current patients had reduced fetal movements.…”

Section: Resultsmentioning

confidence: 99%

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights

et al. 2017

View full text Add to dashboard Cite

Congenital myasthenic syndromes (CMS) are clinically and genetically heterogeneous disorders of neuromuscular transmission. Most are treatable, but certain subtypes worsen with cholinesterase inhibitors. This underlines the importance of genetic diagnosis. Here, we report on cases with genetically proven CMS from Turkey. We retrospectively reviewed our experience of all patients with CMS, referred over a 5-year period (2011–2016) to the Child Neurology Department of Dokuz Eylül University, Izmir, Turkey. In addition, PubMed was searched for published cases of genetically proven CMS originating from Turkey. In total, we identified 43 (8 new patients, 35 recently published patients) cases. Defects in the acetylcholine receptor (n=15; 35%) were the most common type, followed by synaptic basal-lamina associated (n=14; 33%) and presynaptic syndromes (n=10; 23%). We only had 3 cases (7%) who had defects in endplate development. One patient had mutation GFPT1 gene (n=1; 2%). Knowledge on CMS and related genes in Turkey will lead to prompt diagnosis and treatment of these rare neuromuscular disorders.

show abstract

Identification of mutations in theMYO9Agene in patients with congenital myasthenic syndrome

Cited by 48 publications

References 48 publications

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

Novel synaptobrevin‐1 mutation causes fatal congenital myasthenic syndrome

POPDC3 Gene Variants Associate with a New Form of Limb Girdle Muscular Dystrophy

Genetic Landscape of Congenital Myasthenic Syndromes From Turkey: Novel Mutations and Clinical Insights

Contact Info

Product

Resources

About