Clinical and pathological characterization of <scp><i>FLNC</i></scp>‐related myofibrillar myopathy caused by founder variant c.8129G&gt;A in Hong Kong Chinese

Lee, Han-Chih Hencher; Wong, Shun; Sheng, Bun; Pan, Nin-Yuan Keith; Leung, Ying-Kit Frank; Lau, Kwok-Kwong Dominic; Cheng, Yue; Ho, Luen-Cheung; Li, Richard; Lee, Chi-Nam; Tsoi, Tak Hong; Cheung, Yuk-fai; Fu, Yat-Pang Michael; Kan, Nim-Chi Amanda; Chu, Yim-Pui; Au, Wing-Chi Lisa; Yeung, Hon-Ming Jonas; Li, Siu-Hung; Cheung, Chi-Fung Mark; Tong, Hok-Fung; Hung, Ling-Yin Esther; Chan, Tina Yee-Ching; Li, Chi Terence; Tong, Tsz-Yan Tammy; Tong, Tin-Wing Candy; Leung, Ho-Ying Cory; Lee, Ka‐Ho; Yeung, Sung-Yan Sue; Lee, Sau-Yin Blanka; Lau, Tze-Chin Gene; Lam, Ching‐Wan; Mak, Chloe Miu; Chan, Andrew

doi:10.1111/cge.13715

Cited by 6 publications

(6 citation statements)

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“…In the present study, we explore the pathophysiology of the human FLNC p.W2710X mutation [ClinVar: NM_001458.4( FLNC ):c.8130G > A (p.Trp2710Ter); Allele ID: 33353], which in the heterozygous state is the most frequently encountered human myopathy-causing FLNC gene defect in various ethnic groups [ 37 , 86 ]. It must be noted that another mutation mainly appearing in the population of Hong Kong [ClinVar: NM_001458.4( FLNC ):c.8129G > A (p.Trp2710Ter); Allele ID: 682327] leads to the expression of an identical protein variant [ 44 ]. Both truncation mutations result in loss of the 16 carboxy-terminal amino acids, thus impeding the formation of dimers of Ig-like domain 24 of FLNc.…”

Section: Introductionmentioning

confidence: 99%

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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Filamin C (FLNc) is mainly expressed in striated muscle cells where it localizes to Z-discs, myotendinous junctions and intercalated discs. Recent studies have revealed numerous mutations in the FLNC gene causing familial and sporadic myopathies and cardiomyopathies with marked clinical variability. The most frequent myopathic mutation, p.W2710X, which is associated with myofibrillar myopathy, deletes the carboxy-terminal 16 amino acids from FLNc and abolishes the dimerization property of Ig-like domain 24. We previously characterized “knock-in” mice heterozygous for this mutation (p.W2711X), and have now investigated homozygous mice using protein and mRNA expression analyses, mass spectrometry, and extensive immunolocalization and ultrastructural studies. Although the latter mice display a relatively mild myopathy under normal conditions, our analyses identified major mechanisms causing the pathophysiology of this disease: in comparison to wildtype animals (i) the expression level of FLNc protein is drastically reduced; (ii) mutant FLNc is relocalized from Z-discs to particularly mechanically strained parts of muscle cells, i.e. myotendinous junctions and myofibrillar lesions; (iii) the number of lesions is greatly increased and these lesions lack Bcl2-associated athanogene 3 (BAG3) protein; (iv) the expression of heat shock protein beta-7 (HSPB7) is almost completely abolished. These findings indicate grave disturbances of BAG3-dependent and -independent autophagy pathways that are required for efficient lesion repair. In addition, our studies reveal general mechanisms of lesion formation and demonstrate that defective FLNc dimerization via its carboxy-terminal domain does not disturb assembly and basic function of myofibrils. An alternative, more amino-terminally located dimerization site might compensate for that loss. Since filamins function as stress sensors, our data further substantiate that FLNc is important for mechanosensing in the context of Z-disc stabilization and maintenance.

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Section: Introductionmentioning

confidence: 99%

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Schuld

Orfanos

Chevessier

et al. 2020

acta neuropathol commun

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“…The majority of MFM patients follow an autosomal dominant inheritance pattern, while less frequently, the disease is transmitted by autosomal recessive or X-linked dominant/recessive pattern ( 7 – 9 ). There are several case reports of Chinese MFM patients, and one study identified a founder mutation in FLNC gene in 34 patients from Hong Kong area ( 10 – 13 ). In this study, we present the clinical, histological, immunohistochemical, and genetic analysis in 18 Chinese MFM patients diagnosed in our neuromuscular center.…”

Section: Introductionmentioning

confidence: 99%

Expanding the Clinico-Genetic Spectrum of Myofibrillar Myopathy: Experience From a Chinese Neuromuscular Center

Luo

Peng

et al. 2020

Front. Neurol.

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Background: Myofibrillar myopathy is a group of hereditary neuromuscular disorders characterized by dissolution of myofibrils and abnormal intracellular accumulation of Z disc-related proteins. We aimed to characterize the clinical, physiological, pathohistological, and genetic features of Chinese myofibrillar myopathy patients from a single neuromuscular center. Methods: A total of 18 patients were enrolled. Demographic and clinical data were collected. Laboratory investigations, electromyography, and cardiac evaluation was performed. Routine and immunohistochemistry stainings against desmin, αB-crystallin, and BAG3 of muscle specimen were carried out. Finally, next-generation sequencing panel array for genes associated with hereditary neuromuscular disorders were performed. Results: Twelve pathogenic variants in DES, BAG3, FLNC, FHL1, and TTN were identified, of which seven were novel mutations. The novel DES c.1256C>T substitution is a high frequency mutation. The combined recessively/dominantly transmitted c.19993G>T and c.107545delG mutations in TTN gene cause a limb girdle muscular dystrophy phenotype with the classical myofibrillar myopathy histological changes. Conclusions: We report for the first time that hereditary myopathy with early respiratory failure patient can have peripheral nerve and severe spine involvement. The mutation in Ig-like domain 16 of FLNC is associated with the limb girdle type of filaminopathy, and the mutation in Ig-like domain 18 with distal myopathy type. These findings expand the phenotypic and genotypic correlation spectrum of myofibrillar myopathy.

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“… 7 The region directly flanking the p.K2676Pfs*3 mutation detected in our family (GGTGGGCGTGCACGGCCC CAAG A C CCCCTGTGAGGAGGTG, deleted nucleotides are underlined) is very GC-rich (72.5%), and stretches of 4 or 5 guanines or cytosines, often flanked by an adenine or thymine, were identified as hotspots for human mutations. 37 It is interesting to note that also 2 different MFM-causing mutations in Ig-like domain 24 of FLNc are localized in a stretch of 4 guanines flanked on both sides by a thymine (NM_001458.4(FLNC):c.8130G>A and c.8129G>A 4 , 9 ). Both mutations result in the same mutation at the protein level (p.W2710X), indicating that this specific stretch of guanines indeed is a mutation hotspot.…”

Section: Discussionmentioning

confidence: 99%

“…[1][2][3] A subtype of MFM caused by heterozygous mutations in the FLNC gene (MFM5; MIM# 609524) was discovered in 2005, 4 and thereafter, additional families with MFM-filaminopathy were described. [5][6][7][8][9] Main clinical features are progressive skeletal muscle weakness usually manifesting between the fourth and sixth decade of life and respiratory insufficiency in advanced disease stages. MRI reveals a typical pattern of lower limb muscle involvement helpful in differential diagnostics.…”

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confidence: 99%

FLNC-Associated Myofibrillar Myopathy

et al. 2021

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ObjectiveTo determine whether a new indel mutation in the dimerization domain of filamin C (FLNc) causes a hereditary myopathy with protein aggregation in muscle fibers, we clinically and molecularly studied a German family with autosomal dominant myofibrillar myopathy (MFM).MethodsWe performed mutational analysis in 3 generations, muscle histopathology, and proteomic studies of IM protein aggregates. Functional consequences of the FLNC mutation were investigated with interaction and transfection studies and biophysics molecular analysis.ResultsEight patients revealed clinical features of slowly progressive proximal weakness associated with a heterozygous c.8025_8030delCAAGACinsA (p.K2676Pfs*3) mutation in FLNC. Two patients exhibited a mild cardiomyopathy. MRI of skeletal muscle revealed lipomatous changes typical for MFM with FLNC mutations. Muscle biopsies showed characteristic MFM findings with protein aggregation and lesion formation. The proteomic profile of aggregates was specific for MFM-filaminopathy and indicated activation of the ubiquitin-proteasome system (UPS) and autophagic pathways. Functional studies revealed that mutant FLNc is misfolded, unstable, and incapable of forming homodimers and heterodimers with wild-type FLNc.ConclusionsThis new MFM-filaminopathy family confirms that expression of mutant FLNC leads to an adult-onset muscle phenotype with intracellular protein accumulation. Mutant FLNc protein is biochemically compromised and leads to dysregulation of protein quality control mechanisms. Proteomic analysis of MFM protein aggregates is a potent method to identify disease-relevant proteins, differentiate MFM subtypes, evaluate the relevance of gene variants, and identify novel MFM candidate genes.

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Clinical and pathological characterization of FLNC‐related myofibrillar myopathy caused by founder variant c.8129G>A in Hong Kong Chinese

Cited by 6 publications

References 37 publications

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Homozygous expression of the myofibrillar myopathy-associated p.W2710X filamin C variant reveals major pathomechanisms of sarcomeric lesion formation

Expanding the Clinico-Genetic Spectrum of Myofibrillar Myopathy: Experience From a Chinese Neuromuscular Center

FLNC-Associated Myofibrillar Myopathy

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