Novel cofilin-2 (CFL2) four base pair deletion causing nemaline myopathy

Ong, Royston; Alsaman, Abdulaziz; Selcen, Duygu; Arabshahi, Arash; Yau, Kyle S.; Ravenscroft, Gianina; Duff, Rachael M.; Atkinson, Vanessa; Allcock, Richard J. N.; Laing, Nigel G.

doi:10.1136/jnnp-2014-307608

Cited by 25 publications

(24 citation statements)

References 5 publications

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“…Similarly to the present findings, also in the previously reported cases has been demonstrated that the missense mutations had a pathogenetic role leading to a misfolding and accelerated protein degradation . Consistently, nonsense‐mediated decay has been reported for CFL2 truncating changes, strongly pointing to loss of CFL2 function as the underlying mechanism of disease.…”

Section: Discussionsupporting

confidence: 68%

“…We report three new severe cases of CM related to novel inactivating mutations in CFL2 . Only for the cases with null mutations, our patients were more severely affected than previously reported families with CFL2 missense mutations . Morphological features, consistent of thin filaments accumulations and myofibrillar changes, are evocative of the histopathological findings observed in Cfl2 −/− mouse model.…”

Section: Resultsmentioning

confidence: 45%

“…Biallelic mutations in CFL2 are a rare cause of an AR form of NM (MIM #610687). The few reported cases are clinical and morphological heterogeneous leading to early‐onset and rapidly progressive phenotype to a milder condition characterized by limb girdle and axial muscle weakness . Muscle histology shows features of nemaline or myofibrillar myopathy (MFM), as well as coexistence of both of these histopathological changes .…”

Section: Introductionmentioning

confidence: 99%

“…The few reported cases are clinical and morphological heterogeneous leading to early-onset and rapidly progressive phenotype to a milder condition characterized by limb girdle and axial muscle weakness. 8,17,18 Muscle histology shows features of nemaline or myofibrillar myopathy (MFM), as well as coexistence of both of these histopathological changes. 17 Complete loss of cofilin-2 function is generally associated to a severe phenotype, however, the precise mechanism through which cofilin-2 defect leads to different structural abnormalities remains elusive.…”

Section: Introductionmentioning

confidence: 99%

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Expanding the histopathological spectrum of CFL2‐related myopathies

et al. 2018

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Congenital myopathies (CMs) caused by mutation in cofilin-2 gene (CFL2) show phenotypic heterogeneity ranging from early-onset and rapid progressive forms to milder myopathy. Muscle histology is also heterogeneous showing rods and/or myofibrillar changes. Here, we report on three new cases, from two unrelated families, of severe CM related to novel homozygous or compound heterozygous loss-of-function mutations in CFL2. Peculiar histopathological changes showed nemaline bodies and thin filaments accumulations together to myofibrillar changes, which were evocative of the muscle findings observed in Cfl2 knockout mouse model.

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Section: Discussionsupporting

confidence: 68%

Section: Resultsmentioning

confidence: 45%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Expanding the histopathological spectrum of CFL2‐related myopathies

et al. 2018

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“…Cofilin-2 knockout mice display rod-shaped accumulations called nemaline bodies, which consist of thin filament and Z-disc proteins (12). Mutations in cofilin-2 have been identified in patients with nemaline myopathy, similar to the cofilin-2 knockout mouse, resulting in nemaline bodies and progressive muscle weakness (11, 507, 518). Knockdown of cofilin-2 in neonatal rat cardiomyocytes results in an elongation of the thin filaments, indicating a role in actin filament dynamics.…”

Section: M-band: Cross-links Myosin Filaments and Acts As A Hub For Mmentioning

confidence: 99%

Overview of the Muscle Cytoskeleton

Henderson

Gomez

Novak

et al. 2017

Comprehensive Physiology

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Cardiac and skeletal striated muscles are intricately designed machines responsible for muscle contraction. Coordination of the basic contractile unit, the sarcomere, and the complex cytoskeletal networks are critical for contractile activity. The sarcomere is comprised of precisely organized individual filament systems that include thin (actin), thick (myosin), titin, and nebulin. Connecting the sarcomere to other organelles (e.g., mitochondria and nucleus) and serving as the scaffold to maintain cellular integrity are the intermediate filaments. The costamere, on the other hand, tethers the sarcomere to the cell membrane. Unique structures like the intercalated disc in cardiac muscle and the myotendinous junction in skeletal muscle help synchronize and transmit force. Intense investigation has been done on many of the proteins that make up these cytoskeletal assemblies. Yet the details of their function and how they interconnect have just started to be elucidated. A vast number of human myopathies are contributed to mutations in muscle proteins; thus understanding their basic function provides a mechanistic understanding of muscle disorders. In this review, we highlight the components of striated muscle with respect to their interactions, signaling pathways, functions, and connections to disease.

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