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| 2. |
- Kimber, Eva, 1951, et al.
(författare)
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A mutation in the fast skeletal muscle troponin I gene causes myopathy and distal arthrogryposis
- 2006
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Ingår i: Neurology. - : Ovid Technologies (Wolters Kluwer Health). - 1526-632X .- 0028-3878. ; 67:4, s. 597-601
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To describe a three-generation family with distal arthrogryposis associated with myopathy and caused by a mutation in the gene encoding for sarcomeric thin filament protein troponin I, TNNI2. METHODS: The authors performed clinical investigations and reviewed medical records. Muscle biopsy specimens were obtained for morphologic analysis. Genomic DNA was extracted from blood and analyzed for mutations in TNNI2. RESULTS: The five affected individuals had predominantly distal congenital joint contractures, mild facial involvement (mild micrognathia, narrow palpebral fissures), and no detectable muscle weakness. The four affected adults had slightly increased levels of creatine kinase in blood, and muscle biopsy specimens showed findings of myopathy with changes restricted to type 2 fibers. These included variability of muscle fiber size, internalized nuclei, and increased interstitial connective tissue. Analysis of TNNI2 encoding the troponin I isoform expressed in type 2 muscle fibers disclosed a heterozygous three-base in-frame deletion, 2,918-2,920del, skipping the highly conserved lysine at position 176. The mutation was present in all 5 affected individuals but was not identified in any of the 11 unaffected family members. CONCLUSION: Distal arthrogryposis type 1 is genetically heterogeneous, and myopathy due to sarcomeric protein dysfunction may be one underlying cause of the disease.
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| 3. |
- Kimber, Eva, 1951-, et al.
(författare)
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Distal arthrogryposis : clinical and genetic findings
- 2012
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Ingår i: Acta Paediatrica. - : John Wiley & Sons. - 0803-5253 .- 1651-2227. ; 101:8, s. 877-887
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Distal arthrogryposis is characterized by congenital contractures predominantly in hands and feet. Mutations in sarcomeric protein genes are involved in several types of distal arthrogryposis. Our aim is to describe clinical and molecular genetic findings in individuals with distal arthrogryposis and evaluate the genotype-phenotype correlation.METHOD: We investigated 39 patients from 21 families. Clinical history, including neonatal findings, joint involvement and motor function, was documented. Clinical examination was performed including evaluation of muscle strength. Molecular genetic investigations were carried out in 19 index cases. Muscle biopsies from 17 patients were analysed.RESULTS: A pathogenic mutation was found in six families with 19 affected family members with autosomal dominant inheritance and in one child with sporadic occurrence. In three families and in one child with sporadic form, the identified mutation was de novo. Muscle weakness was found in 17 patients. Ambulation was affected in four patients and hand function in 28. Fourteen patients reported pain related to muscle and joint affection.CONCLUSION: The clinical findings were highly variable between families and also within families. Mutations in the same gene were found in different syndromes suggesting varying clinical penetrance and expression, and different gene mutations were found in the same clinical syndrome demonstrating genetic heterogeneity.
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| 4. |
- Li, Mingxin, et al.
(författare)
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Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
- 2006
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Ingår i: Neuromuscular Disorders. - : Elsevier BV. - 0960-8966 .- 1873-2364. ; 16:11, s. 782-791
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Tidskriftsartikel (refereegranskat)abstract
- The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.
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| 6. |
- Moslemi, Ali-Reza, et al.
(författare)
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Glycogenin-1 deficiency and inactivated priming of glycogen synthesis.
- 2010
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Ingår i: The New England journal of medicine. - : Massachusetts Medical Society. - 1533-4406 .- 0028-4793. ; 362:13, s. 1203-10
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Tidskriftsartikel (refereegranskat)abstract
- Glycogen, which serves as a major energy reserve in cells, is a large, branched polymer of glucose molecules. We describe a patient who had muscle weakness, associated with the depletion of glycogen in skeletal muscle, and cardiac arrhythmia, associated with the accumulation of abnormal storage material in the heart. The skeletal muscle showed a marked predominance of slow-twitch, oxidative muscle fibers and mitochondrial proliferation. Western blotting showed the presence of unglucosylated glycogenin-1 in the muscle and heart. Sequencing of the glycogenin-1 gene, GYG1, revealed a nonsense mutation in one allele and a missense mutation, Thr83Met, in the other. The missense mutation resulted in inactivation of the autoglucosylation of glycogenin-1 that is necessary for the priming of glycogen synthesis in muscle.
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| 7. |
- Ochala, Julien, et al.
(författare)
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Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
- 2007
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Ingår i: Journal of Physiology. - : Wiley. - 0022-3751 .- 1469-7793. ; 581:Pt 3, s. 1283-92
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Tidskriftsartikel (refereegranskat)abstract
- A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force–pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force–pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces alteration in myosin–actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.
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| 8. |
- Ohlsson, Monica, et al.
(författare)
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Hereditary myopathy with early respiratory failure associated with a mutation in A-band titin
- 2012
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 135:6, s. 1682-1694
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Tidskriftsartikel (refereegranskat)abstract
- Hereditary myopathy with early respiratory failure and extensive myofibrillar lesions has been described in sporadic and familial cases and linked to various chromosomal regions. The mutated gene is unknown in most cases. We studied eight individuals, from three apparently unrelated families, with clinical and pathological features of hereditary myopathy with early respiratory failure. The investigations included clinical examination, muscle histopathology and genetic analysis by whole exome sequencing and single nucleotide polymorphism arrays. All patients had adult onset muscle weakness in the pelvic girdle, neck flexors, respiratory and trunk muscles, and the majority had prominent calf hypertrophy. Examination of pulmonary function showed decreased vital capacity. No signs of cardiac muscle involvement were found. Muscle histopathological features included marked muscle fibre size variation, fibre splitting, numerous internal nuclei and fatty infiltration. Frequent groups of fibres showed eosinophilic inclusions and deposits. At the ultrastructural level, there were extensive myofibrillar lesions with marked Z-disc alterations. Whole exome sequencing in four individuals from one family revealed a missense mutation, g.274375T > C; p.Cys30071Arg, in the titin gene (TTN). The mutation, which changes a highly conserved residue in the myosin binding A-band titin, was demonstrated to segregate with the disease in all three families. High density single nucleotide polymorphism arrays covering the entire genome demonstrated sharing of a 6.99 Mb haplotype, located in chromosome region 2q31 including TTN, indicating common ancestry. Our results demonstrate a novel and the first disease-causing mutation in A-band titin associated with hereditary myopathy with early respiratory failure. The typical histopathological features with prominent myofibrillar lesions and inclusions in muscle and respiratory failure early in the clinical course should be incentives for analysis of TTN mutations.
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| 10. |
- Oldfors, Anders, 1951, et al.
(författare)
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Myopathies associated with myosin heavy chain mutations
- 2004
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Ingår i: Acta myologica : myopathies and cardiomyopathies : official journal of the Mediterranean Society of Myology / edited by the Gaetano Conte Academy for the study of striated muscle diseases. - : The Mediterranean Society of Myology. - 1128-2460. ; 23:2, s. 90-6
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Tidskriftsartikel (refereegranskat)abstract
- Myosin, a molecular motor, converts chemical energy into mechanical force. The motor domain of myosin heavy chain (MyHC) includes an ATP binding region with ATPase activity and an actin-binding region. Motor function is achieved by conformational changes, at hydrolysis, of ATP causing a shift in the angle between the actin binding head and the rod region of the molecule. The elongated alpha-helical coiled-coil rod region of MyHC molecules constitutes the major part of the thick filaments of the sarcomere. Three major MyHC isoforms are expressed in human skeletal muscle (type I, MYH7, expressed in type 1 fibres; IIa, MYH2, expressed in 2A fibres; IIx, MYH1, expressed in 2B fibres). While mutations in slow/beta cardiac MyHC (MYH7) are a common cause of familial hypertrophic cardiomyopathy, no skeletal myopathies have, until recently, been associated with mutations in MyHC. A heterozygous mutation, Glu706Lys, in the core of the head of MyHC IIa is associated with a familial congenital myopathy, which, in most instances, has shown mild phenotypic expression in children but progressive course in some adults. There is a relationship between the level of expression of mutated MyHC IIa and muscle pathology. Some adults with a progressive course show muscle fibres with rimmed vacuoles and filaments of the type seen in inclusion body myositis/myopathy (IBM). Endurance training in a group of affected patients caused a shift in the expression of myosin from fast (IIx) to slow (I) isoforms but no reduction in the expression of MyHC IIa. A heterozygous mutation, Arg1845Trp, in the distal rod region of slow myosin (type I, MYH7) is associated with familial congenital myopathy, with large deposits of MyHC I in the subsarcolemmal region of type 1 muscle fibres, "Myosin storage myopathy". These patients showed slowly progressive muscle weakness but no overt cardiomyopathy. These two muscle diseases, which are caused by mutations in MyHC, form the basis of a novel entity: "Myosin myopathies".
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