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ABSTRACT: The main diagnostic feature of congenital fibre type disproportion is that type 1 fibres are consistently smaller than type 2 fibres in the absence of other histological abnormalities. Mutations in the TPM3, RYR1 and ACTA1 genes are the most common established genetic causes. There has been one previous report of congenital fibre type disproportion due to a mutation in TPM2, although some atypical histological features were present. We present two cases in which novel de novo missense mutations in TPM2 are associated with marked fibre size disproportion. The finding of typical histological changes of congenital fibre type disproportion in association with a p.Ser61Pro mutation confirms that TPM2 can cause typical congenital fibre type disproportion. Although not seen on light microscopy studies, protein inclusions typical of small 'caps' were found on electron microscopy in a second patient with a p.Ala155Val mutation in TPM2. This case emphasises the importance of electron microscopy in patients with presumed congenital fibre type disproportion, to exclude the presence of caps, nemaline bodies or minicores, which, if present, may be very helpful in guiding genetic analysis.
Neuromuscular Disorders 07/2012; · 2.80 Impact Factor
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ABSTRACT: Large muscle genes are often sequenced using complementary DNA (cDNA) made from muscle messenger RNA (mRNA) to reduce the cost and workload associated with sequencing from genomic DNA. Two potential barriers are the availability of a frozen muscle biopsy, and difficulties in detecting nonsense mutations due to nonsense-mediated mRNA decay (NMD). We present patient examples showing that use of MyoD-transduced fibroblasts as a source of muscle-specific mRNA overcomes these potential difficulties in sequencing large muscle-related genes.
Muscle & Nerve 08/2011; 44(2):280-2. · 2.37 Impact Factor
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Eppie M Yiu,
Alfred Klausegger, Leigh B Waddell,
Nikolaus Grasern,
Lyn Lloyd,
Kim Tran,
Kathryn N North,
Johann W Bauer,
Penelope McKelvie,
C W Chow,
Monique M Ryan,
Dedee F Murrell
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ABSTRACT: Epidermolysis bullosa associated with muscular dystrophy is a rare, autosomal recessive form of epidermolysis bullosa simplex caused by mutations in the plectin gene, PLEC1. We describe a phenotypically mild case due to compound heterozygous mutations in PLEC1 (2677_2685del and the novel mutation Q1644X). Clinical features included mild skin blistering since birth, slowly progressive and late-onset upper limb-predominant weakness, facial weakness, ptosis, incomplete ophthalmoplegia, and paroxysmal atrial fibrillation.
Muscle & Nerve 07/2011; 44(1):135-41. · 2.37 Impact Factor
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Leigh B Waddell,
Jenny Tran,
Xi F Zheng,
Carsten G Bönnemann,
Ying Hu,
Frances J Evesson,
Monkol Lek,
Susan Arbuckle,
Min-Xia Wang,
Robert L Smith,
Kathryn N North,
Nigel F Clarke
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ABSTRACT: FHL1, BAG3, MATR3 and PTRF are recently identified myopathy genes associated with phenotypes that overlap muscular dystrophy. TCAP is a rare reported cause of muscular dystrophy not routinely screened in most centres. We hypothesised that these genes may account for patients with undiagnosed forms of muscular dystrophy in Australia. We screened a large cohort of muscular dystrophy patients for abnormalities in FHL1 (n=102) and TCAP (n=100) and selected patients whose clinical features overlapped the phenotypes previously described for BAG3 (n=9), MATR3 (n=15) and PTRF (n=7). We found one FHL1 mutation (c.311G>A, p.C104Y) in a boy with rapidly progressive muscle weakness and reducing body myopathy who was initially diagnosed with muscular dystrophy. We identified no pathogenic mutations in BAG3, MATR3, PTRF or TCAP. In conclusion, we have excluded these five genes as common causes of muscular dystrophy in Australia. Patients with reducing body myopathy may be initially diagnosed as muscular dystrophy.
Neuromuscular Disorders 06/2011; 21(11):776-81. · 2.80 Impact Factor
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Leigh B Waddell,
Frances A Lemckert,
Xi F Zheng,
Jenny Tran,
Frances J Evesson,
Joanne M Hawkes,
Angela Lek,
Neil E Street,
Peihui Lin,
Nigel F Clarke,
Andrew P Landstrom,
Michael J Ackerman,
Noah Weisleder,
Jianjie Ma,
Kathryn N North,
Sandra T Cooper
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ABSTRACT: Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and the newly identified protein mitsugumin 53 (MG53). Mitsugumin 53 accumulates at sites of membrane damage, and MG53-knockout mice display a progressive muscular dystrophy. This study explored the expression and localization of MG53 in human skeletal muscle, how membrane repair proteins are modulated in various forms of muscular dystrophy, and whether MG53 is a primary cause of human muscle disease. Mitsugumin 53 showed variable sarcolemmal and/or cytoplasmic immunolabeling in control human muscle and elevated levels in dystrophic patients. No pathogenic MG53 mutations were identified in 50 muscular dystrophy patients, suggesting that MG53 is unlikely to be a common cause of muscular dystrophy in Australia. Western blot analysis confirmed upregulation of MG53, as well as of dysferlin, annexin A1, and caveolin-3 to different degrees, in different muscular dystrophies. Importantly, MG53, annexin A1, and dysferlin localize to the t-tubule network and show enriched labeling at longitudinal tubules of the t-system in overstretch. Our results suggest that longitudinal tubules of the t-system may represent sites of physiological membrane damage targeted by this membrane repair complex.
Journal of Neuropathology and Experimental Neurology 03/2011; 70(4):302-13. · 4.26 Impact Factor
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Tanya L Butler,
Giorgia Esposito,
Gillian M Blue,
Andrew D Cole,
Mauro W Costa, Leigh B Waddell,
Gina Walizada,
Gary F Sholler,
Edwin P Kirk,
Michael Feneley,
Richard P Harvey,
David S Winlaw
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ABSTRACT: Congenital heart disease (CHD) represents one of the most common birth defects, but the genetic causes remain largely unknown. Mutations in GATA4, encoding a zinc finger transcription factor with a pivotal role in heart development, have been associated with CHD in several familial cases and a small subset of sporadic patients. To estimate the pathogenetic role of GATA4 in CHD, we screened for mutations in 357 unrelated patients with different congenital heart malformations. In addition to nine synonymous changes, we identified two known (A411V and D425N) and two novel putative mutations (G69D and P163R) in five patients with atrial or ventricular septal defects that were not seen in control subjects. The four mutations did not show altered GATA4 transcriptional activity in synergy with the transcription factors NKX2-5 and TBX20. Our data expand the spectrum of mutations associated with cardiac septal defects but do not support GATA4 mutations as a common cause of CHD.
Genetic Testing and Molecular Biomarkers 12/2010; 14(6):797-802. · 1.11 Impact Factor
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ABSTRACT: We report a third patient with typical cap myopathy due to a heterozygous TPM3 mutation, confirming the importance of this causal association. The p.R168C TPM3 mutation we identified has been reported in two previous patients. The histological changes associated with this mutation vary widely from typical cap myopathy with near complete type 1 predominance (two patients), to typical congenital fibre-type disproportion without protein inclusions (one patient). We performed 2D-gel electrophoresis using muscle biopsies from two patients with the p.R168C mutation and show that mutant protein accounts for around 50% of alpha-tropomyosin(slow) in sarcomeres, consistent with a dominant negative mechanism of disease pathogenesis.
Neuromuscular Disorders 07/2010; 20(7):464-6. · 2.80 Impact Factor
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Nigel F Clarke, Leigh B Waddell,
Sandra T Cooper,
Margaret Perry,
Robert L L Smith,
Andrew J Kornberg,
Francesco Muntoni,
Suzanne Lillis,
Volker Straub,
Kate Bushby,
Michela Guglieri,
Mary D King,
Michael A Farrell,
Isabelle Marty,
Joel Lunardi,
Nicole Monnier,
Kathryn N North
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ABSTRACT: The main histological abnormality in congenital fiber type disproportion (CFTD) is hypotrophy of type 1 (slow twitch) fibers compared to type 2 (fast twitch) fibers. To investigate whether mutations in RYR1 are a cause of CFTD we sequenced RYR1 in seven CFTD families in whom the other known causes of CFTD had been excluded. We identified compound heterozygous changes in the RYR1 gene in four families (five patients), consistent with autosomal recessive inheritance. Three out of five patients had ophthalmoplegia, which may be the most specific clinical indication of mutations in RYR1. Type 1 fibers were at least 50% smaller, on average, than type 2 fibers in all biopsies. Recessive mutations in RYR1 are a relatively common cause of CFTD and can be associated with extreme fiber size disproportion.
Human Mutation 07/2010; 31(7):E1544-50. · 5.69 Impact Factor
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Edwin P Kirk,
Margaret Sunde,
Mauro W Costa,
Scott A Rankin,
Orit Wolstein,
M Leticia Castro,
Tanya L Butler,
Changbaig Hyun,
Guanglan Guo,
Robyn Otway, [......],
Christopher Hayward,
Anne Keogh,
Peter Macdonald,
Lyn Griffiths,
Diane Fatkin,
Gary F Sholler,
Aaron M Zorn,
Michael P Feneley,
David S Winlaw,
Richard P Harvey
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ABSTRACT: The T-box family transcription factor gene TBX20 acts in a conserved regulatory network, guiding heart formation and patterning in diverse species. Mouse Tbx20 is expressed in cardiac progenitor cells, differentiating cardiomyocytes, and developing valvular tissue, and its deletion or RNA interference-mediated knockdown is catastrophic for heart development. TBX20 interacts physically, functionally, and genetically with other cardiac transcription factors, including NKX2-5, GATA4, and TBX5, mutations of which cause congenital heart disease (CHD). Here, we report nonsense (Q195X) and missense (I152M) germline mutations within the T-box DNA-binding domain of human TBX20 that were associated with a family history of CHD and a complex spectrum of developmental anomalies, including defects in septation, chamber growth, and valvulogenesis. Biophysical characterization of wild-type and mutant proteins indicated how the missense mutation disrupts the structure and function of the TBX20 T-box. Dilated cardiomyopathy was a feature of the TBX20 mutant phenotype in humans and mice, suggesting that mutations in developmental transcription factors can provide a sensitized template for adult-onset heart disease. Our findings are the first to link TBX20 mutations to human pathology. They provide insights into how mutation of different genes in an interactive regulatory circuit lead to diverse clinical phenotypes, with implications for diagnosis, genetic screening, and patient follow-up.
The American Journal of Human Genetics 09/2007; 81(2):280-91. · 10.60 Impact Factor
