Congenital muscular dystrophies: What is new?

Zambon, Alberto A.; Muntoni, Francesco

doi:10.1016/j.nmd.2021.07.009

Cited by 39 publications

(55 citation statements)

References 52 publications

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“…As clinical and histological findings resembled previously published cases of dogs with CMD [9,10,20], we hypothesized that the phenotype in the affected dog was due to a variant in one of the known CMD candidate genes [1]. We sequenced the genome of the affected dog and searched for private homozygous and heterozygous variants that were not present in the genome sequences of 786 control dogs and nine wolves (Table 1 and Supplementary Tables S1 and S2).…”

Section: Genetic Analysismentioning

confidence: 81%

“…We sequenced the genome of the affected dog and searched for private homozygous and heterozygous variants that were not present in the genome sequences of 786 control dogs and nine wolves (Table 1 and Supplementary Tables S1 and S2). [1] 1 0…”

Section: Genetic Analysismentioning

confidence: 99%

“…Congenital muscular dystrophies (CMDs) are a heterogeneous group of inherited neuromuscular disorders. They show a wide variety of clinical features including early onset weakness and hypotonia, as well as delay or arrest of motor milestones and loss of those same milestones later in the course of the disease [1]. Serum creatine kinase (CK) activity is often elevated, suggesting disruption of the permeability of the sarcoplasmic membrane [2].…”

Section: Introductionmentioning

confidence: 99%

“…Muscle biopsies typically show dystrophic features [3]. To date, variants in at least 39 different candidate genes are recognized that lead to CMD in human medicine [1]. Among the most commonly observed CMDs are those resulting from variants in genes coding for structural proteins of the basal lamina and extracellular matrix, such as type VI collagen or laminin α2 [4].…”

Section: Introductionmentioning

confidence: 99%

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LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy

Christen

Indzhova

Guo

et al. 2021

Genes

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A 4-month-old, male Italian Greyhound with clinical signs of a neuromuscular disease was investigated. The affected dog presented with an abnormal short-strided gait, generalized muscle atrophy, and poor growth since 2-months of age. Serum biochemistry revealed a marked elevation in creatine kinase activity. Electrodiagnostic testing supported a myopathy. Histopathology of muscle biopsies confirmed a dystrophic phenotype with excessive variability in myofiber size, degenerating fibers, and endomysial fibrosis. A heritable form of congenital muscular dystrophy (CMD) was suspected, and a genetic analysis initiated. We sequenced the genome of the affected dog and compared the data to that of 795 control genomes. This search revealed a private homozygous nonsense variant in LAMA2, XM_022419950.1:c.3285G>A, predicted to truncate 65% of the open reading frame of the wild type laminin α2 protein, XP_022275658.1:p.(Trp1095*). Immunofluorescent staining performed on muscle cryosections from the affected dog confirmed the complete absence of laminin α2 in skeletal muscle. LAMA2 loss of function variants were shown to cause severe laminin α2-related CMD in humans, mouse models, and in one previously described dog. Our data together with current knowledge on other species suggest the LAMA2 nonsense variant as cause for the CMD phenotype in the investigated dog.

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Section: Genetic Analysismentioning

confidence: 81%

Section: Genetic Analysismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy

Christen

Indzhova

Guo

et al. 2021

Genes

View full text Add to dashboard Cite

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“…Early-onset MD-C1A is an autosomal recessive disorder caused by mutation in LAMA2 gene which leads to loss of α2 subunit of laminin-211 protein. Laminins are heterotrimeric proteins composed of α, β and γ subunits, and laminin-211 (also called merosin) is predominantly expressed in skeletal muscle as an important tissue component of ECM (83,86). Laminins are essential for basement membrane assembly and insufficient assembly of laminin network causes poor connection to the muscle fibers, which may be one of causes of MDC1A (87).…”

Section: Congenital Muscle Dystrophymentioning

confidence: 99%

BMP1.3 protein as potential target in treatment of fibrosis

Nikšić¹,

Kufner²

2021

Rad Hrvatske akademije znanosti i umjetnosti

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Bone morphogenetic protein 1 (BMP1) belongs to the procollagen C proteinase (PCP) family of proteases involved in development and pattern formation in various organisms. BMP1 proteinases mediate the cleavage of carboxyl peptides from procollagen molecules, which is a crucial step in fibrillar collagen synthesis. From six described alternatively spliced variants of human Bmp1 gene, only BMP1.3 protein was detected in human plasma and elevated plasma levels of this protein were found in pathological conditions such as chronic kidney disease and acute myocardial infarction. Since BMP1 is required to convert pro-collagen to collagen, its inhibition is a potential intervention for treating fibrosis. Inhibition of BMP1.3 was shown to decrease the progression of liver fibrosis in an animal model of liver cirrhosis. One of the major inflammatory signaling molecules involved in fibrogenesis in various organs is transforming growth factor beta 1 (TGFβ1), which expression is elevated in various models of induced fibrosis. Many studies have revealed that BMP1 proteases play a key role in regulation of TGFβ activation. Here, we discuss BMP1.3 inhibition as a potential treatment in different pathological conditions related to the fibrosis. Testing BMP1.3 inhibition in these models indicates that the anti-BMP1.3 antibody targets relevant pathways in the development of fibrosis in different organs.

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The congenital muscular dystrophies

Topaloğlu,

Poorshiri

2023

Annals of the Child Neurology Society

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BackgroundCongenital muscular dystrophies (CMDs) are genetically and clinically heterogeneous inherited conditions. Onset is typically within the first year of life. Most CMDs are autosomal recessive, except for de novo dominant mutations in LMNA‐related muscular dystrophy and some collagen‐6‐associated disorders.ResultsCMD is characterized by progressive muscular weakness, hypotonia, multiple contractures with a variable degree, spinal stiffness, delay in motor milestones acquisition, and histologically dystrophic lesions. Also, some forms of CMD may feature structural and myelination abnormalities on brain magnetic resonance imaging, intellectual impairment, and structural abnormalities of the eye. Muscle biopsy specimens exhibit a dystrophic pattern, but the appearance is quite variable depending on the different stages and severity of the disorder. The prevalence of CMD is estimated to be one in 100 000 people. Over the last few years, with advances in molecular genetic diagnostics, knowledge about neuromuscular disorders, particularly CMDs, has increased dramatically. Thus, the incidence may be higher than originally thought.ConclusionThis article reviews the recent achievements related to the clinical, diagnostic, pathogenic, and therapeutic aspects of CMDs.

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Congenital muscular dystrophies: What is new?

Cited by 39 publications

References 52 publications

LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy

LAMA2 Nonsense Variant in an Italian Greyhound with Congenital Muscular Dystrophy

BMP1.3 protein as potential target in treatment of fibrosis

The congenital muscular dystrophies

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