Identification of a novel heterozygous <i>DYSF</i> variant in a large family with a dominantly‐inherited dysferlinopathy

Folland, Chiara; Johnsen, R.; Gomez, Adriana Botero; Trajanoski, Daniel; Davis, Mark; Moore, Ursula; Straub, V.; Barresi, Rita; Guglieri, Michela; Hayhurst, Hannah; Schaefer, Andrew M.; Laing, Nigel G.; Lamont, Philipa J.; Ravenscroft, Gianina

doi:10.1111/nan.12846

Cited by 6 publications

(8 citation statements)

References 69 publications

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“…The variants associated with a dominant inheritance are usually loss-of-function, but missense variants have also been reported. In calpainopathy and dysferlinopathy, a dual inheritance mode has also been suggested, with most of the variants transmitted recessively and a few transmitted dominantly, both missense and loss-of-function variants [ 5 , 6 , 47 , 48 ]. For some diseases, a semidominant inheritance pattern has been well described.…”

Section: Dual Inheritance Mode Vs Symptomatic Heterozygousmentioning

confidence: 99%

“…A dominant negative (DN) effect means that the expression of a mutant protein interferes with the activity of a wild-type protein. The DN model has been suggested to operate in calpainopathy [ 5 ] and dysferlinopathy [ 6 ], for example. Here, not only the deleteriousness of the variant but also its structural location plays a role.…”

Section: Molecular Background and Possible Influencing Factorsmentioning

confidence: 99%

“…Although overall very rare, a heterozygous symptomatic state is quite common in some diseases. Also, individuals who carry just one variant of the disease-causing gene and who display quite a severe phenotype are often not defined as symptomatic carriers per se; rather, they are classified as an example of a dominant inheritance with a milder disease form [ 5 , 6 ]. Indeed, sometimes only a fine line exists between these two conditions.…”

Section: Introductionmentioning

confidence: 99%

“…Symptoms are usually located somewhere on the continuum between healthy individuals and patients carrying two variants. Correspondingly, symptomatic heterozygotes for genes related to neuromuscular disorders usually present with myalgias [ 5 , 6 ], mild muscular atrophy [ 11 ], and for hematological diseases with jaundice and mild symptoms of anemia [ 12 ] or familiar mild ptosis among the individuals with only one variant causative for congenital myasthenic syndrome (CMS), but where also cases of recessive CMS occurred [ 13 ]. In some cases, only some abnormalities in the laboratory tests may be detected [ 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

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The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Kalyta,

Stelmaszczyk,

Szczęśniak

et al. 2023

Genes

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Heterozygous carriers of pathogenic/likely pathogenic variants in autosomal recessive disorders seem to be asymptomatic. However, in recent years, an increasing number of case reports have suggested that mild and unspecific symptoms can occur in some heterozygotes, as symptomatic heterozygotes have been identified across different disease types, including neurological, neuromuscular, hematological, and pulmonary diseases. The symptoms are usually milder in heterozygotes than in biallelic variants and occur “later in life”. The status of symptomatic heterozygotes as separate entities is often disputed, and alternative diagnoses are considered. Indeed, often only a thin line exists between dual, dominant, and recessive modes of inheritance and symptomatic heterozygosity. Interestingly, recent population studies have found global disease effects in heterozygous carriers of some genetic variants. What makes the few heterozygotes symptomatic, while the majority show no symptoms? The molecular basis of this phenomenon is still unknown. Possible explanations include undiscovered deep-splicing variants, genetic and environmental modifiers, digenic/oligogenic inheritance, skewed methylation patterns, and mutational burden. Symptomatic heterozygotes are rarely reported in the literature, mainly because most did not undergo the complete diagnostic procedure, so alternative diagnoses could not be conclusively excluded. However, despite the increasing accessibility to high-throughput technologies, there still seems to be a small group of patients with mild symptoms and just one variant of autosomes in biallelic diseases. Here, we present some examples, the current state of knowledge, and possible explanations for this phenomenon, and thus argue against the existing dominant/recessive classification.

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Section: Dual Inheritance Mode Vs Symptomatic Heterozygousmentioning

confidence: 99%

Section: Molecular Background and Possible Influencing Factorsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Kalyta,

Stelmaszczyk,

Szczęśniak

et al. 2023

Genes

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“…Several other studies confirmed that typical patient biopsies contain necrotic fibres, regenerative ones, and connective or fat tissue [42][43][44]. One of them compared the phenotypes of early-onset (EO) and late-onset (LO) patients.…”

Section: Muscle Biopsymentioning

confidence: 87%

Portrait of Dysferlinopathy: Diagnosis and Development of Therapy

Bouchard,

Tremblay

2023

JCM

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Dysferlinopathy is a disease caused by a dysferlin deficiency due to mutations in the DYSF gene. Dysferlin is a membrane protein in the sarcolemma and is involved in different functions, such as membrane repair and vesicle fusion, T-tubule development and maintenance, Ca2+ signalling, and the regulation of various molecules. Miyoshi Myopathy type 1 (MMD1) and Limb–Girdle Muscular Dystrophy 2B/R2 (LGMD2B/LGMDR2) are two possible clinical presentations, yet the same mutations can cause both presentations in the same family. They are therefore grouped under the name dysferlinopathy. Onset is typically during the teenage years or young adulthood and is characterized by a loss of Achilles tendon reflexes and difficulty in standing on tiptoes or climbing stairs, followed by a slow progressive loss of strength in limb muscles. The MRI pattern of patient muscles and their biopsies show various fibre sizes, necrotic and regenerative fibres, and fat and connective tissue accumulation. Recent tools were developed for diagnosis and research, especially to evaluate the evolution of the patient condition and to prevent misdiagnosis caused by similarities with polymyositis and Charcot–Marie–Tooth disease. The specific characteristic of dysferlinopathy is dysferlin deficiency. Recently, mouse models with patient mutations were developed to study genetic approaches to treat dysferlinopathy. The research fields for dysferlinopathy therapy include symptomatic treatments, as well as antisense-mediated exon skipping, myoblast transplantation, and gene editing.

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Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy

Mavillard

Servián‐Morilla

Dofash

et al. 2023

Brain

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The extracellular matrix (ECM) has an important role in the development and maintenance of skeletal muscle, and several muscle diseases are associated with the dysfunction of ECM elements. MAMDC2 is a putative ECM protein and its role in cell proliferation has been investigated in certain cancer types. However, its participation in skeletal muscle physiology has not been previously studied. We describe 17 individuals with an autosomal dominant muscular dystrophy belonging to two unrelated families in which different heterozygous truncating variants in the last exon of MAMDC2 co-segregate correctly with the disease. The radiological aspect of muscle involvement resembles that of COL6 myopathies with fat replacement at the peripheral rim of vastii muscles. In this cohort, a subfascial and peri-tendinous pattern is observed in upper and lower limb muscles. Here we show that MAMDC2 is expressed in adult skeletal muscle and differentiating muscle cells where it appears to localise to the sarcoplasm and myonuclei. In addition, we show it is secreted by myoblasts and differentiating myotubes into to the extracellular compartment. The last exon encodes a disordered region with a polar residue compositional bias loss of which likely induces a toxic effect of the mutant protein. The precise mechanisms by which the altered MAMDC2 proteins cause disease remains to be determined. MAMDC2 is a skeletal muscle disease-associated protein. Its role in muscle development and ECM-muscle communication remains to be fully elucidated. Screening of the last exon of MAMDC2 should be considered in patients presenting with autosomal dominant muscular dystrophy, particularly in those with a subfascial radiological pattern of muscle involvement.

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Identification of a novel heterozygous DYSF variant in a large family with a dominantly‐inherited dysferlinopathy

Cited by 6 publications

References 69 publications

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

The Spectrum of the Heterozygous Effect in Biallelic Mendelian Diseases—The Symptomatic Heterozygote Issue

Portrait of Dysferlinopathy: Diagnosis and Development of Therapy

Ablation of the carboxy-terminal end of MAMDC2 causes a distinct muscular dystrophy

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