Guglieri, M., Magri, F. & Comi, G. P. Molecular etiopathogenesis of limb girdle muscular and congenital muscular dystrophies: boundaries and contiguities. Clin. Chim. Acta 361, 54-79
ABSTRACT The muscular dystrophies are a heterogeneous group of inherited disorders characterized by progressive muscle wasting and weakness. These disorders present a large clinical variability regarding age of onset, patterns of skeletal muscle involvement, heart damage, rate of progression and mode of inheritance. Difficulties in classification are often caused by the relatively common sporadic occurrence of autosomal recessive forms as well as by intrafamilial clinical variability. Furthermore recent discoveries, particularly regarding the proteins linking the sarcolemma to components of the extracellular matrix, have restricted the gap existing between limb girdle (LGMD) and congenital muscular dystrophies (CMD). Therefore a renewed definition of boundaries between these two groups is required. Molecular genetic studies have demonstrated different causative mutations in the genes encoding a disparate collection of proteins involved in all aspects of muscle cell biology. These novel skeletal muscle genes encode highly diverse proteins with different localization within or at the surface of the skeletal muscle fibre, such as the sarcolemmal muscle membrane (dystrophin, sarcoglycans, dysferlin, caveolin-3), the extracellular matrix (alpha2 laminin, collagen VI), the sarcomere (telethonin, myotilin, titin, nebulin and ZASP), the muscle cytosol (calpain-3, TRIM32), the nucleus (emerin, lamin A/C) and the glycosilation pathway enzymes (fukutin and fukutin related proteins). The accumulating knowledge about the role of these different proteins in muscle pathology has led to a profound change in the original phenotype-based classification and shed new light on the molecular pathogenesis of these disorders.
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- "LGMD2E, LGMD2F and LGMD2C forms respectively (Guglieri et al., 2005; Daniele et al., 2007). Mutations in LAMA2 gene are known to be involved in the MDC1A form representing that which is most frequent in cases of congenital muscular dystrophy. "
ABSTRACT: In this study, we detected new sequence variations in LAMA2 and SGCG genes in 5 ethnic populations, and analysed their effect on enhancer composition and mRNA structure. PCR amplification and DNA sequencing were performed and followed by bioinformatics analyses using ESEfinder as well as MFOLD software. We found 3 novel sequence variations in the LAMA2 (c.3174+22_23insAT and c.6085 +12delA) and SGCG (c. (*) 102A/C) genes. These variations were present in 210 tested healthy controls from Tunisian, Moroccan, Algerian, Lebanese and French populations suggesting that they represent novel polymorphisms within LAMA2 and SGCG genes sequences. ESEfinder showed that the c. (*) 102A/C substitution created a new exon splicing enhancer in the 3'UTR of SGCG genes, whereas the c.6085 +12delA deletion was situated in the base pairing region between LAMA2 mRNA and the U1snRNA spliceosomal components. The RNA structure analyses showed that both variations modulated RNA secondary structure. Our results are suggestive of correlations between mRNA folding and the recruitment of spliceosomal components mediating splicing, including SR proteins. The contribution of common sequence variations to mRNA structural and functional diversity will contribute to a better study of gene expression.Genetics and Molecular Biology 03/2010; 33(1):190-7. DOI:10.1590/S1415-47572010005000008 · 0.88 Impact Factor
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- "Further diagnostics using DNA analysis were discussed. DNA analysis, aimed at providing confirmation of mutation in the affected gene(s), is necessary to be able to offer carrier or pre-symptomatic testing to other family members [2,11,12]. We discussed this topic with the patient and her sons but they declined further DNA analysis. "
ABSTRACT: Myopathies can be sub-classified into congenital, hereditary, mitochondrial, and secondary myopathies.Congenital myopathies are usually diagnosed post partal or in early childhood. Manifestation in adolescence is uncommon and most cases occur as sporadic mutations. Therefore, there is a risk of under diagnosing this disease in middle-aged patients showing pain, dysfunction, recurrent trauma or falls, where muscle atrophy is seen as a secondary injury. Our report is about a 54 year old Caucasian woman with an extended history of pain, loss of function and weakness in her right shoulder. The clinical picture showed a frozen right shoulder. The main finding was a marked limb-muscle atrophy of both delta- und biceps-muscles and a rotator cuff tear that had developed over years. Previous medical consultations attributed the atrophy to recurrent falls, shoulder dysfunction and pain. Conservative treatment (analgesics, physiotherapy, training) had failed.The familiar anamnesis was free of any neurological diseases or other genetic diseases.MRI showed a sub-total proximal muscular limb atrophy and a rotator cuff tear in both shoulders. An incision-biopsy of the right delta- and biceps-muscle revealed a chronical myopathy. The level of creatinkinasis was expected to be high but measurements showed values only slightly above normal. Immunohistochemistry, eventually revealed a mild form of LGMD (type 2I). Due to the pattern of symptoms and diagnostic results we described the case as atypical LGMD. Our case presents a phenotype of a late onset of limb girdle muscular dystrophy syndrome associated with shoulder pain and dysfunction and recurrent falls. This kind of disease is not very common. In particular, muscle atrophy in the elderly is generally seen as a secondary injury. This case should remind us of the importance of a differential diagnosis of a late onset of muscular dystrophy-syndrome in the elderly, since an early diagnosis offers more treatment options, therefore preventing a rapid progression.Cases Journal 01/2009; 1(1):402. DOI:10.1186/1757-1626-1-402
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- "MIM] 600900; g-SG, SGCG, MIM] 608896; d-SG, SGCD, MIM] 601411), the membrane repair process (dysferlin, DYSF, MIM] 603009), the sarcomere (telethonin, TCAP, MIM] 604488; and titin, TTN, MIM] 188840), the muscle cytosol (calpain-3, CAPN3, MIM] 114240; and TRIM32, MIM] 602290), and the glycosylation pathway enzymes (Fukutin related protein, FKRP, MIM] 606596; and Protein O-Mannosyltransferase 2, POMT2, MIM] 607439) [Guglieri et al., 2005] "
ABSTRACT: Limb girdle muscular dystrophies (LGMD) are characterized by genetic and clinical heterogeneity: seven autosomal dominant and 12 autosomal recessive loci have so far been identified. Aims of this study were to evaluate the relative proportion of the different types of LGMD in 181 predominantly Italian LGMD patients (representing 155 independent families), to describe the clinical pattern of the different forms, and to identify possible correlations between genotype, phenotype, and protein expression levels, as prognostic factors. Based on protein data, the majority of probands (n=72) presented calpain-3 deficiency; other defects were as follows: dysferlin (n=31), sarcoglycans (n=32), alpha-dystroglycan (n=4), and caveolin-3 (n=2). Genetic analysis identified 111 different mutations, including 47 novel ones. LGMD relative frequency was as follows: LGMD1C (caveolin-3) 1.3%; LGMD2A (calpain-3) 28.4%; LGMD2B (dysferlin) 18.7%; LGMD2C (gamma-sarcoglycan) 4.5%; LGMD2D (alpha-sarcoglycan) 8.4%; LGMD2E (beta-sarcoglycan) 4.5%; LGMD2F (delta-sarcoglycan) 0.7%; LGMD2I (Fukutin-related protein) 6.4%; and undetermined 27.1%. Compared to Northern European populations, Italian patients are less likely to be affected with LGMD2I. The order of decreasing clinical severity was: sarcoglycanopathy, calpainopathy, dysferlinopathy, and caveolinopathy. LGMD2I patients showed both infantile noncongenital and mild late-onset presentations. Age at disease onset correlated with variability of genotype and protein levels in LGMD2B. Truncating mutations determined earlier onset than missense substitutions (20+/-5.1 years vs. 36.7+/-11.1 years; P=0.0037). Similarly, dysferlin absence was associated with an earlier onset when compared to partial deficiency (20.2+/-standard deviation [SD] 5.2 years vs. 28.4+/-SD 11.2 years; P=0.014).Human Mutation 02/2008; 29(2):258-66. DOI:10.1002/humu.20642 · 5.05 Impact Factor