Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive <i>TNNT3</i> splice variant

Sandaradura, Sarah A.; Bournazos, Adam; Mallawaarachchi, Amali; Cummings, Beryl B.; Waddell, Leigh B.; Jones, Kristi; Troedson, Christopher; Sudarsanam, Annapurna; Nash, Benjamin; Peters, Gregory B.; Algar, Elizabeth; MacArthur, Daniel G.; North, Klaus; Brammah, Susan; Charlton, Amanda; Laing, Nigel G.; Wilson, Meredith; Davis, Mark; Cooper, Sandra T.

doi:10.1002/humu.23385

Cited by 54 publications

(57 citation statements)

References 15 publications

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“…Table S3 outlines the 13 articles that describe pathological results of muscle biopsies in patients with distal arthrogryposes found in our literature review. Three articles revealed definitive pathological diagnoses that helped to underscore the clinical diagnosis (Davidson et al, 2012; Oldfors et al, ; Sandaradura et al, ). All concerned clinical and pathological diagnoses of congenital myopathies associated with AMC ( TPM2 delK7, MYH2 , recessive loss of function mutation TNNT3 ).…”

Section: Investigationsmentioning

confidence: 99%

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Dieterich

Tanno

Kimber³

et al. 2019

American J of Med Genetics Pt C

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Arthrogryposis multiplex congenita, or AMC, is a clinical sign defined as congenital contractures of at least two joint levels. These joint contractures are always secondary to diminished fetal movement which can have numerous causes that affect any part of the anatomical structures implicated in movement: the central nervous system, the anterior horn cell, the nerve, the neuromuscular junction, the muscle, or the joint itself.Make a precise diagnosis of the cause in a patient with multiple joint contractures is therefore challenging. The aim of this article is to summarize the use and diagnostic value of common examinations and analyses performed postnatally in patients affected by AMC from a literature review. We also compare this data with results from our clinical practice. Even though it is difficult to give precise guidelines today, it appears that genetic studies, such as whole exome or genome analysis in all patients and chromosomal microarray analysis in patients with intellectual disability and AMC should be preferred as first tier investigations over EMG and muscle biopsy. K E Y W O R D S AMC, arthrogryposis multiplex congenita, diagnosis, genetic investigations, next generation sequencing

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Section: Investigationsmentioning

confidence: 99%

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Dieterich

Tanno

Kimber³

et al. 2019

American J of Med Genetics Pt C

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“…While nemaline bodies are the key diagnostic feature of NM, there is no correlation between nemaline body number and disease severity ( Malfatti and Romero, 2016 ). Mutations in at least 12 genes have been implicated in NM: 8 of the 12 genes encode sarcomere thin filament proteins, including ACTA1, NEB, TPM2, TPM3, CFL2, TPM3, LMOD3, TNNT1, and TNNT3; 3 genes encode Kelch-like proteins, namely KBTBD13, KLHL40, and KLHL41; and 1 gene encodes MYPN, a component of the Z disc ( Gupta and Beggs, 2014 ; Kondo et al, 2012 ; Malfatti and Romero, 2016 ; Miyatake et al, 2017 ; Nilipour et al, 2018 ; Sandaradura et al, 2018 ; Sewry et al, 2019 ). It remains unclear how mutations in these individual genes contribute to NM development and particularly to the mechanisms that result in the formation of nemaline bodies and muscle weakness.…”

Section: Introductionmentioning

confidence: 99%

Cofilin Loss in Drosophila Muscles Contributes to Muscle Weakness through Defective Sarcomerogenesis during Muscle Growth

Balakrishnan¹,

Yu²,

Chin³

et al. 2020

Cell Reports

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SUMMARY Sarcomeres, the fundamental contractile units of muscles, are conserved structures composed of actin thin filaments and myosin thick filaments. How sarcomeres are formed and maintained is not well understood. Here, we show that knockdown of Drosophila cofilin ( DmCFL ), an actin depolymerizing factor, disrupts both sarcomere structure and muscle function. The loss of DmCFL also results in the formation of sarcomeric protein aggregates and impairs sarcomere addition during growth. The activation of the proteasome delays muscle deterioration in our model. Furthermore, we investigate how a point mutation in CFL2 that causes nemaline myopathy (NM) in humans affects CFL function and leads to the muscle phenotypes observed in vivo . Our data provide significant insights to the role of CFLs during sarcomere formation, as well as mechanistic implications for disease progression in NM patients.

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“…Nemaline myopathy (NM) is one of the most common congenital myopathies and is caused by pathogenic variants in one of at least twelve different genes [4,18,27,29,37,52,55,64,69,74,75,91]. Patient muscle biopsies show accumulation of Z-disc and thin filament associated proteins into aggregates called nemaline bodies, usually accompanied by disorganization of the muscle Z discs [14,80,83].…”

Section: Introductionmentioning

confidence: 99%

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Laitila

McNamara

Wingate

et al. 2020

acta neuropathol commun

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Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb Y2303H, Y935X , has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.

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Nemaline myopathy and distal arthrogryposis associated with an autosomal recessive TNNT3 splice variant

Cited by 54 publications

References 15 publications

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

The diagnostic workup in a patient with AMC: Overview of the clinical evaluation and paraclinical analyses with review of the literature

Cofilin Loss in Drosophila Muscles Contributes to Muscle Weakness through Defective Sarcomerogenesis during Muscle Growth

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

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