Distal myopathy with upper limb predominance caused by
            <i>filamin C</i>
            haploinsufficiency

Guergueltcheva, Velina; Peeters, Kris; Baets, Jonathan; Groote, Chantal Ceuterick‐de; Martin, J. J.; Suls, Arvid; Vriendt, Els De; Mihaylova, Violeta; Chamova, Teodora; Almeida-Souza, Le­onardo; Ydens, Elke; Tzekov, Christo; Hadjidekov, G.; Господинова, Мариана; Storm, Katrien; Reyniers, Edwin; Bichev, Stoyan; Ven, Peter F.M. van der; Fürst, Dieter O.; Mitev, Vanio; Lochmüller, Hanns; Timmerman, Vincent; Tournev, Ivailo; Jonghe, Peter De; Jordanova, Albena

doi:10.1212/wnl.0b013e31823dc51e

Cited by 54 publications

(80 citation statements)

References 26 publications

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“…Haploinsufficiency has been suggested as the most probable reason for the disease phenotype in a number of patients with FLNC-induced myopathy. 15 Yet, this is clearly not the case here as the paternal family, expressing only the normal allele, is healthy. In the database of genomic variant, more than 12 cases with full or partial deletion of the FLNC gene have been reported, suggesting that happloinsufficiency may not be a common Western blot analysis, using antibodies directed to the C and N terminus of Filamin C showing that no protein was produced using both variants.…”

Section: Discussionmentioning

confidence: 87%

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

et al. 2016

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In the vast majority of pediatric patients with dilated cardiomyopathy, the specific etiology is unknown. Studies on families with dilated cardiomyopathy have exemplified the role of genetic factors in cardiomyopathy etiology. In this study, we applied wholeexome sequencing to members of a non-consanguineous family affected by a previously unreported congenital dilated cardiomyopathy syndrome necessitating early-onset heart transplant. Exome analysis identified compound heterozygous variants in the FLNC gene. Histological analysis of the cardiac muscle demonstrated marked sarcomeric and myofibrillar abnormalities, and immunohistochemical staining demonstrated the presence of Filamin C aggregates in cardiac myocytes. We conclude that biallelic variants in FLNC can cause congenital dilated cardiomyopathy. As the associated clinical features of affected patients are mild, and can be easily overlooked, testing for FLNC should be considered in children presenting with dilated cardiomyopathy.

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Section: Discussionmentioning

confidence: 87%

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

et al. 2016

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“…In a recently reported Bulgarian family with a frame-shifting deletion mutation in exon 30 of FLNC (p.F1720LfsX63) leading to haploinsufficiency, the disease was associated with distal muscle weakness primarily in the upper limbs with lower limb involvement upon disease progression [18]. It manifests in adulthood between the ages of 20–57 years.…”

Section: Clinical Aspectsmentioning

confidence: 99%

“…Filaminopathies are recently identified progressive skeletal myopathies manifesting initially by bilateral weakness in either proximal leg muscles or in distal upper limb muscles spreading to other muscle groups and in some forms eventually resulting in tetraparesis and wheelchair dependence [6, 18, 22, 57]. Three distinct types of filaminopathy are recognized.…”

Section: Introductionmentioning

confidence: 99%

“…In contrast, mutations in the actin-binding domain (ABD) of FLNc are responsible for the second disease variant that is initially characterized by weakness and wasting of distal muscles, especially intrinsic hand muscles, manifesting in the third decade of life [6]. An intermediate filaminopathy phenotype affecting primarily distal muscles of the upper and lower limbs has recently been described [18]. Muscle biopsies of patients with aggregation-causing FLNC mutations show disintegration of myofibrils and formation of desmin-positive protein aggregates within muscle fibers [30, 39].…”

Section: Introductionmentioning

confidence: 99%

“…Thus far MFM has been associated with mutations in seven genes ( DES, MYOT , LDB3 / ZASP , CRYAB , BAG3 , FLNC and FHL1 [33, 40–42]). Muscle biopsies from patients with the second filaminopathy variant show non-specific myopathic abnormalities without MFM pathology [6], while histological evaluation in cases with the intermediate variant indicated disease-associated myofibrillar abnormalities, but desmin-positive protein aggregates required for the diagnosis of MFM were not detected [18]. …”

Section: Introductionmentioning

confidence: 99%

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Filamin C-related myopathies: pathology and mechanisms

et al. 2012

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The term filaminopathy was introduced after a truncating mutation in the dimerization domain of filamin C (FLNc) was shown to be responsible for a devastating muscle disease. Subsequently, the same mutation was found in patients from diverse ethnical origins, indicating that this specific alteration is a mutational hot spot. Patients initially present with proximal muscle weakness, while distal and respiratory muscles become affected with disease progression. Muscle biopsies of these patients show typical signs of myofibrillar myopathy, including disintegration of myofibrils and aggregation of several proteins into distinct intracellular deposits. Highly similar phenotypes were observed in patients with other mutations in Ig-like domains of FLNc that result in expression of a noxious protein. Biochemical and biophysical studies showed that the mutated domains acquire an abnormal structure causing decreased stability and eventually becoming a seed for abnormal aggregation with other proteins. The disease usually presents only after the fourth decade of life possibly as a result of ageing-related impairments in the machinery that is responsible for disposal of damaged proteins. This is confirmed by mutations in components of this machinery that cause a highly similar phenotype. Transfection studies of cultured muscle cells reflect the events observed in patient muscles and, therefore, may provide a helpful model for testing future dedicated therapeutic strategies. More recently, FLNC mutations were also found in families with a distal myopathy phenotype, caused either by mutations in the actin-binding domain of FLNc that result in increased actin-binding and non-specific myopathic abnormalities without myofibrillar myopathy pathology, or a nonsense mutation in the rod domain that leads to RNA instability, haploinsufficiency with decreased expression levels of FLNc in the muscle fibers and myofibrillar abnormalities, but not to the formation of desmin-positive protein aggregates required for the diagnosis of myofibrillar myopathy.

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Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

Peeters

Palaima

Pelayo‐Negro

et al. 2016

Annals of Neurology

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Our findings demonstrate that the isolated genetic entity CMT2G is caused by a missense mutation in LRSAM1 and should be reclassified as CMT2P. MRI of lower-limb musculature can be used to detect minimal signs of the disease. Transcriptome analysis of patients' cells highlights novel molecular players associated with LRSAM1 dysfunction, and reveals pathways and therapeutic targets shared with amyotrophic lateral sclerosis and Alzheimer disease. Ann Neurol 2016;80:823-833.

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Distal myopathy with upper limb predominance caused by filamin C haploinsufficiency

Cited by 54 publications

References 26 publications

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

Congenital dilated cardiomyopathy caused by biallelic mutations in Filamin C

Filamin C-related myopathies: pathology and mechanisms

Charcot–Marie–Tooth disease type 2G redefined by a novel mutation in LRSAM1

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