The Experts below are selected from a list of 743652 Experts worldwide ranked by ideXlab platform
Vincenzo Nigro - One of the best experts on this subject based on the ideXlab platform.
-
Disease rescue and increased lifespan in a model of cardiomyopathy and muscular dystrophy by combined AAV treatments. PLoS One 2009;4:e5051
2016Co-Authors: Carmen Vitiello, Stefania Faraso, Gerardo Nigro, Alberto Auricchio, Nicolina Cristina Sorrentino, G Di Salvo, Edoardo Nusco, Luisa Cutillo, Vincenzo NigroAbstract:Background: The BIO14.6 hamster is an excellent animal model for inherited cardiomyopathy, because of its lethal and well-documented course, due to a spontaneous deletion of Delta-Sarcoglycan gene promoter and first exon. The muscle disease is progressive and average lifespan is 11 months, because heart slowly dilates towards heart failure. Methodology/Principal Findings: Based on the ability of adeno-associated viral (AAV) vectors to transduce heart together with skeletal muscle following systemic administration, we delivered human Delta-Sarcoglycan cDNA into male BIO14.6 hamsters by testing different ages of injection, routes of administration and AAV serotypes. Body-wide restoration of delta-SG expression was associated with functional reconstitution of the sarcoglycan complex and with significant lowering of centralized nuclei and fibrosis in skeletal muscle. Motor ability and cardiac functions were completely rescued. However, BIO14.6 hamsters having less than 70 % of fibers recovering sarcoglycan developed cardiomyopathy, even if the total rescued protein was normal. When we used serotype 2/8 in combination with serotype 2/1, lifespan was extended up to 22 months with sustained heart function improvement. Conclusions/Significance: Our data support multiple systemic administrations of AAV as a general therapeutic strategy fo
-
Mutation Carriers
2015Co-Authors: Sarcoglycan Gene, Vincenzo NigroAbstract:Mutations in the human alpha-sarcoglycan gene on chro-mosome 17q21.2 have been shown to cause a severe childhood autosomal recessive muscular dystrophy, a less severe limb girdle muscular dystrophy, exercise intoler-ance, or asymptomatic hyperCKemia. Here, we describe the clinical findings in a German family harboring a 371 T> C (Ile124Thr) missense mutation in the alpha-sarcoglycan gene. Whereas our index patient, an 11-year-old girl homozygous for this mutation, presented with a severe Duchenne-like phenotype, 7 out of 12 heterozy-gous mutation carriers from three generations showed mild to moderate scapular winging. In analogy to symp-tomatic female dystrophinopathy carriers, our results suggest that heterozygous alpha-sarcoglycan gene muta-tion carriers can be symptomatic with selective muscle weakness. This finding may be attributed to an addi-tional negative variation in a yet unknown modifier gene essential to the function of the sarcoglycan complex in shoulder girdle muscles. Ann Neurol 2003;54:674–678 Autosomal recessive limb–girdle muscular dystrophies (LGMD) are a heterogeneous group of genetic diseases with a wide spectrum of clinical involvement and se-verity (see Bushby, 1999, and Bonnemann and Finkel, 2002, for reviews).1,2 Alpha-sarcoglycan, initially called adhalin, is a 50kDa component of the dystrophin-associated sarcoglycan complex that functions as a 1:1: 1:1 heterotetramer with beta, gamma, and Delta-Sarcoglycan at the sarcolemma.3,4 Mutations affecting any of the sarcoglycan genes disrupt this complex and cause muscle fiber degeneration and autosomal reces-sive limb–girdle muscular dystrophies.5–10 A broad spectrum of phenotypes have been associated with mu-tations in the human alpha-sarcoglycan gene on chro-mosome 17q21.2 that range from severe to mild limb– girdle muscular dystrophy (LGMD 2D), exercise intolerance, or asymptomatic hyperCKemia.11–14 This report describes the clinical findings in a homozygous and 12 heterozygous carriers of a 371 T C (Ile124Thr) missense mutation in the alpha-sarcoglycan gene
-
Molecular bases of autosomal recessive limb-girdle muscular dystrophies
2015Co-Authors: Vincenzo NigroAbstract:Limb-girdle muscular dystrophies (LGMD) are a hetero-geneous group of genetically determined disorders with a primary or predominant involvement of the pelvic or shoulder girdle musculature. The clinical course is char-acterized by great variability, ranging from severe forms with rapid onset and progression to very mild forms allowing affected people to have fairly normal life spans and activity levels. Sixteen loci have been so far identi-fied, six autosomal dominant and ten autosomal recessive. Linkage analyses indicate that there is further genetic heterogeneity both for dominant as well as for recessive LGMD. The dominant forms (LGMD1) are generally milder and relatively rare, representing less than 10 % of all LGMD. The autosomal recessive forms (LGMD2) are much more common, having a cumulative prevalence of 1:15,000 with a number of geographical differences. The product of ten autosomal recessive LGMD genes has so far been identified. They are: calpain-3 (LGMD2A), dys-ferlin (LGMD2B), alpha-sarcoglycan (LGMD2D), beta-sarcoglycan (LGMD2E), gamma-sarcoglycan (LGMD2C), Delta-Sarcoglycan (LGMD2F), telethonin (LGMD2G), TRIM32 (LGMD2H), fukutin-related protein (LGMD2I) and titin (LGMD2J). There are, however, at least 25 % of families who can be excluded from any known locus. The present review is devoted to outline the present advance-ments in the molecular bases of autosomal recessive LGMD. Key words: Limb-girdle muscular dystrophies; sarcoglycan
-
δ-Sarcoglycan is required for early zebrafish muscle organization
Experimental cell research, 2004Co-Authors: Jeffrey R. Guyon, Vincenzo Nigro, Alycia N. Mosley, Susan J. Jun, Federica Montanaro, Leta S. Steffen, Yi Zhou, Len I. Zon, Louis M KunkelAbstract:Mutations in sarcoglycans (alpha-, beta-, gamma-, and delta-) have been linked with limb girdle muscular dystrophy (LGMD) types 2C-F in humans. We have cloned the zebrafish orthologue encoding Delta-Sarcoglycan and mapped the gene to linkage group 21. The predicted zebrafish Delta-Sarcoglycan protein is highly homologous with its human orthologue including conservation of two of the three predicted glycosylation sites. Like other members of the dystrophin-associated protein complex (DAPC), Delta-Sarcoglycan localizes to the sarcolemmal membrane of the myofiber in adult zebrafish, but is more apparent at the myosepta in developing embryos. Zebrafish embryos injected with morpholinos against Delta-Sarcoglycan were relatively inactive at 5 dpf, their myofibers were disorganized, and swim bladders uninflated. Immunohistochemical and immunoblotting experiments show that delta-, beta-, and gamma-sarcoglycans were all downregulated in the morphants, whereas dystrophin expression was unaffected. Whereas humans lacking Delta-Sarcoglycan primarily show adult phenotypes, our results suggest that Delta-Sarcoglycan plays a role in early zebrafish muscle development.
-
Evaluation of cardiac and respiratory involvement in sarcoglycanopathies.
Neuromuscular disorders : NMD, 2001Co-Authors: Luisa Politano, Vincenzo Nigro, Serenella Papparella, Nigro G., L. Passamano, Vito R. Petretta, P.f Rambaldi, Pasquale Raia, Antonella PiniAbstract:Sarcoglycanopathies constitute a subgroup of limb-girdle recessive muscular dystrophies due to defects in sarcoglycan complex that comprises five distinct transmembrane proteins called alpha-, beta-, gamma-, delta-and epsilon-sarcoglycans. As it is well known that sarcoglycans are expressed both in heart and in skeletal muscles and a complete deficiency in Delta-Sarcoglycan is the cause of the Syrian hamster BIO.14 cardiomyopathy, we studied cardiac and respiratory involvement in 20 patients with sarcoglycanopathies by clinical, electrocardiographic, echocardiographic, scintigraphic and spirometric assessments. A normal heart function was found in 31.3% of all patients; a preclinical cardiomyopathy in 43.7%; an arrhythmogenic cardiomyopathy in 6.3% and initial signs of dilated cardiomyopathy in 18.7%. In one patient the data were examined retrospectively. No correlation was found between cardiac and skeletal muscle involvement. With reference to the type of sarcoglycanopathy, signs of hypoxic myocardial damage occurred in beta-, gamma- and Delta-Sarcoglycanopathies, while initial signs of a dilated cardiomyopathy in gamma- and Delta-Sarcoglycanopathies were found. A normal respiratory function was observed in 23.5% of all patients, a mild impairment in 35.4%, a moderate impairment in 29.4%, and a severe impairment in 11.7%.
Mariz Vainzof - One of the best experts on this subject based on the ideXlab platform.
-
Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.
Nature genetics, 2000Co-Authors: E. S. Moreira, Mariz Vainzof, Mayana Zatz, Oscar T. Suzuki, Georgine Faulkner, Giorgio Valle, Tim Wiltshire, Antje Nilforoushan, Roger H. Reeves, Maria Rita Passos-buenoAbstract:Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
-
A first missense mutation in the delta sarcoglycan gene associated with a severe phenotype and frequency of limb-girdle muscular dystrophy type 2F (LGMD2F) in Brazilian sarcoglycanopathies.
Journal of medical genetics, 1998Co-Authors: E. S. Moreira, Mariz Vainzof, Suely Kazue Nagahashi Marie, Vincenzo Nigro, Mayana Zatz, Maria Rita Passos-buenoAbstract:Among the heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (AR LGMDs), the sarcoglycanopathies (LGMD2C-2F) represent a subgroup characterised by defects in the gamma, alpha, beta, and delta sarcoglycan genes, respectively. Genotype-phenotype correlations in these forms of AR LGMD are important to enhance our understanding of protein function. Regarding LGMD2F, only two homozygous frameshift mutations have been reported to date in patients with a severe phenotype. In the present report, through screening 23 unrelated AR LGMD patients, we identified three subjects with LGMD2F, two with a previously reported frameshift mutation and the other homozygous for a new missense mutation in the delta sarcoglycan gene. Interestingly, this new mutation is also associated with a severe clinical course. In addition, our results suggest that this form of severe AR LGMD is not very rare in our population.
-
the sarcoglycan complex in the six autosomal recessive limb girdle muscular dystrophies
Human Molecular Genetics, 1996Co-Authors: Mariz Vainzof, E. S. Moreira, Suely Kazue Nagahashi Marie, Elizabeth M. Mcnally, Maria Rita Passosbueno, M Canovas, R C M Pavanello, Louise V B Anderson, Carsten G Bonnemann, Vincenzo NigroAbstract:To enhance our understanding of the autosomal recessive limb-girdle muscular dystrophy (LGMD), patients from six genetically distinct forms (LGMD2A to LGMD2F) were studied with antibodies directed against four sarcoglycan subunits (alpha-, beta-, gamma-, delta-SG), dystrophin, beta-dystroglycan (beta-DG) and merosin. All patients with LGMD2A and 2B had a mild clinical course while those with a primary sarcoglycan mutation (LGMD2C to 2F) had a range of clinical severity. Dystrophin and merosin immunofluorescence pattern was positive in patients with all six AR LGMDs. The majority of patients with a severe Duchenne-like phenotype presented total absence of the SG complex. However, some exceptions were found in 13q linked patients, indicating that the presence of a certain labelling for components of the SG may not be prognostic for a milder phenotype. The observation that the primary absence of alpha-SG results in the total absence of beta- and delta-SG but not of gamma-SG suggests that the alpha-, beta- and delta-subunits of sarcoglycan may be more closely associated. A secondary reduction in dystrophin amount was seen in patients with primary sarcoglycan mutations, which was most marked in patients with primary beta-, gamma- and delta-SG deficiencies. In contrast, beta-DG staining was retained in all patients, suggesting that the association between SG and DG subcomplexes is not so strong. Based on the above findings, we have refined the model for the interaction among the known glycoproteins of the sarcoglycan complex, within the DGC.
-
autosomal recessive limb girdle muscular dystrophy lgmd2f is caused by a mutation in the delta sarcoglycan gene
Nature Genetics, 1996Co-Authors: Vincenzo Nigro, Mariz Vainzof, Giulio Piluso, Angela Belsito, E De Sa Moreira, L Politano, A A Puca, Maria Rita Passosbueno, Mayana ZatzAbstract:Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited neuromuscular disorders characterized by proximal muscular weakness of the pelvic and shoulder girdles and a variable progression with symptoms, ranging from very severe to mild1,2. One autosomal dominant (LGMD1 A, at chromosome 5q22.3–31.3) (ref. 3) and five autosomal recessive (AR) loci responsible for this phenotype have been identified: LGMD2A at 15q (ref. 4); LGMD2B at 2p (ref. 5), LGMD2C at 13q (ref. 6), LGMD2D at 17q (ref. 7) and LGMD2E at 4q (refs 8, 9). In the muscle membrane, dystrophin associates with several proteins and glycoproteins organized in two main subcomplexes: the dystroglycan (DG) and sarcoglycan (SG) complexes9, 10–14. The genes for LGMD2C, LGMD2D and LGMD2E code for proteins of the SG complex7, 8, 15–17. We recently mapped a sixth AR form of LGMD, LGMD2F, to chromosome 5q33–3418 in two Brazilian families. In the same chromosomal interval we also mapped the δSG gene, encoding a novel 35-kD component of the sarcoglycan (SG) complex19. We now show that a homozygous mutation in the δSG gene (a single nucleotide deletion that alters its reading frame) is the cause of LGMD2F.
E. S. Moreira - One of the best experts on this subject based on the ideXlab platform.
-
Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.
Nature genetics, 2000Co-Authors: E. S. Moreira, Mariz Vainzof, Mayana Zatz, Oscar T. Suzuki, Georgine Faulkner, Giorgio Valle, Tim Wiltshire, Antje Nilforoushan, Roger H. Reeves, Maria Rita Passos-buenoAbstract:Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
-
A first missense mutation in the delta sarcoglycan gene associated with a severe phenotype and frequency of limb-girdle muscular dystrophy type 2F (LGMD2F) in Brazilian sarcoglycanopathies.
Journal of medical genetics, 1998Co-Authors: E. S. Moreira, Mariz Vainzof, Suely Kazue Nagahashi Marie, Vincenzo Nigro, Mayana Zatz, Maria Rita Passos-buenoAbstract:Among the heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (AR LGMDs), the sarcoglycanopathies (LGMD2C-2F) represent a subgroup characterised by defects in the gamma, alpha, beta, and delta sarcoglycan genes, respectively. Genotype-phenotype correlations in these forms of AR LGMD are important to enhance our understanding of protein function. Regarding LGMD2F, only two homozygous frameshift mutations have been reported to date in patients with a severe phenotype. In the present report, through screening 23 unrelated AR LGMD patients, we identified three subjects with LGMD2F, two with a previously reported frameshift mutation and the other homozygous for a new missense mutation in the delta sarcoglycan gene. Interestingly, this new mutation is also associated with a severe clinical course. In addition, our results suggest that this form of severe AR LGMD is not very rare in our population.
-
the sarcoglycan complex in the six autosomal recessive limb girdle muscular dystrophies
Human Molecular Genetics, 1996Co-Authors: Mariz Vainzof, E. S. Moreira, Suely Kazue Nagahashi Marie, Elizabeth M. Mcnally, Maria Rita Passosbueno, M Canovas, R C M Pavanello, Louise V B Anderson, Carsten G Bonnemann, Vincenzo NigroAbstract:To enhance our understanding of the autosomal recessive limb-girdle muscular dystrophy (LGMD), patients from six genetically distinct forms (LGMD2A to LGMD2F) were studied with antibodies directed against four sarcoglycan subunits (alpha-, beta-, gamma-, delta-SG), dystrophin, beta-dystroglycan (beta-DG) and merosin. All patients with LGMD2A and 2B had a mild clinical course while those with a primary sarcoglycan mutation (LGMD2C to 2F) had a range of clinical severity. Dystrophin and merosin immunofluorescence pattern was positive in patients with all six AR LGMDs. The majority of patients with a severe Duchenne-like phenotype presented total absence of the SG complex. However, some exceptions were found in 13q linked patients, indicating that the presence of a certain labelling for components of the SG may not be prognostic for a milder phenotype. The observation that the primary absence of alpha-SG results in the total absence of beta- and delta-SG but not of gamma-SG suggests that the alpha-, beta- and delta-subunits of sarcoglycan may be more closely associated. A secondary reduction in dystrophin amount was seen in patients with primary sarcoglycan mutations, which was most marked in patients with primary beta-, gamma- and delta-SG deficiencies. In contrast, beta-DG staining was retained in all patients, suggesting that the association between SG and DG subcomplexes is not so strong. Based on the above findings, we have refined the model for the interaction among the known glycoproteins of the sarcoglycan complex, within the DGC.
Mayana Zatz - One of the best experts on this subject based on the ideXlab platform.
-
Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.
Nature genetics, 2000Co-Authors: E. S. Moreira, Mariz Vainzof, Mayana Zatz, Oscar T. Suzuki, Georgine Faulkner, Giorgio Valle, Tim Wiltshire, Antje Nilforoushan, Roger H. Reeves, Maria Rita Passos-buenoAbstract:Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
-
A first missense mutation in the delta sarcoglycan gene associated with a severe phenotype and frequency of limb-girdle muscular dystrophy type 2F (LGMD2F) in Brazilian sarcoglycanopathies.
Journal of medical genetics, 1998Co-Authors: E. S. Moreira, Mariz Vainzof, Suely Kazue Nagahashi Marie, Vincenzo Nigro, Mayana Zatz, Maria Rita Passos-buenoAbstract:Among the heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (AR LGMDs), the sarcoglycanopathies (LGMD2C-2F) represent a subgroup characterised by defects in the gamma, alpha, beta, and delta sarcoglycan genes, respectively. Genotype-phenotype correlations in these forms of AR LGMD are important to enhance our understanding of protein function. Regarding LGMD2F, only two homozygous frameshift mutations have been reported to date in patients with a severe phenotype. In the present report, through screening 23 unrelated AR LGMD patients, we identified three subjects with LGMD2F, two with a previously reported frameshift mutation and the other homozygous for a new missense mutation in the delta sarcoglycan gene. Interestingly, this new mutation is also associated with a severe clinical course. In addition, our results suggest that this form of severe AR LGMD is not very rare in our population.
-
autosomal recessive limb girdle muscular dystrophy lgmd2f is caused by a mutation in the delta sarcoglycan gene
Nature Genetics, 1996Co-Authors: Vincenzo Nigro, Mariz Vainzof, Giulio Piluso, Angela Belsito, E De Sa Moreira, L Politano, A A Puca, Maria Rita Passosbueno, Mayana ZatzAbstract:Limb-girdle muscular dystrophies (LGMD) are a heterogeneous group of inherited neuromuscular disorders characterized by proximal muscular weakness of the pelvic and shoulder girdles and a variable progression with symptoms, ranging from very severe to mild1,2. One autosomal dominant (LGMD1 A, at chromosome 5q22.3–31.3) (ref. 3) and five autosomal recessive (AR) loci responsible for this phenotype have been identified: LGMD2A at 15q (ref. 4); LGMD2B at 2p (ref. 5), LGMD2C at 13q (ref. 6), LGMD2D at 17q (ref. 7) and LGMD2E at 4q (refs 8, 9). In the muscle membrane, dystrophin associates with several proteins and glycoproteins organized in two main subcomplexes: the dystroglycan (DG) and sarcoglycan (SG) complexes9, 10–14. The genes for LGMD2C, LGMD2D and LGMD2E code for proteins of the SG complex7, 8, 15–17. We recently mapped a sixth AR form of LGMD, LGMD2F, to chromosome 5q33–3418 in two Brazilian families. In the same chromosomal interval we also mapped the δSG gene, encoding a novel 35-kD component of the sarcoglycan (SG) complex19. We now show that a homozygous mutation in the δSG gene (a single nucleotide deletion that alters its reading frame) is the cause of LGMD2F.
Maria Rita Passos-bueno - One of the best experts on this subject based on the ideXlab platform.
-
Limb-girdle muscular dystrophy type 2G is caused by mutations in the gene encoding the sarcomeric protein telethonin.
Nature genetics, 2000Co-Authors: E. S. Moreira, Mariz Vainzof, Mayana Zatz, Oscar T. Suzuki, Georgine Faulkner, Giorgio Valle, Tim Wiltshire, Antje Nilforoushan, Roger H. Reeves, Maria Rita Passos-buenoAbstract:Autosomal recessive limb-girdle muscular dystrophies (AR LGMDs) are a genetically heterogeneous group of disorders that affect mainly the proximal musculature. There are eight genetically distinct forms of AR LGMD, LGMD 2A-H (refs 2-10), and the genetic lesions underlying these forms, except for LGMD 2G and 2H, have been identified. LGMD 2A and LGMD 2B are caused by mutations in the genes encoding calpain 3 (ref. 11) and dysferlin, respectively, and are usually associated with a mild phenotype. Mutations in the genes encoding gamma-(ref. 14), alpha-(ref. 5), beta-(refs 6,7) and delta (ref. 15)-sarcoglycans are responsible for LGMD 2C to 2F, respectively. Sarcoglycans, together with sarcospan, dystroglycans, syntrophins and dystrobrevin, constitute the dystrophin-glycoprotein complex (DGC). Patients with LGMD 2C-F predominantly have a severe clinical course. The LGMD 2G locus maps to a 3-cM interval in 17q11-12 in two Brazilian families with a relatively mild form of AR LGMD (ref. 9). To positionally clone the LGMD 2G gene, we constructed a physical map of the 17q11-12 region and refined its localization to an interval of 1.2 Mb. The gene encoding telethonin, a sarcomeric protein, lies within this candidate region. We have found that mutations in the telethonin gene cause LGMD 2G, identifying a new molecular mechanism for AR LGMD.
-
A first missense mutation in the delta sarcoglycan gene associated with a severe phenotype and frequency of limb-girdle muscular dystrophy type 2F (LGMD2F) in Brazilian sarcoglycanopathies.
Journal of medical genetics, 1998Co-Authors: E. S. Moreira, Mariz Vainzof, Suely Kazue Nagahashi Marie, Vincenzo Nigro, Mayana Zatz, Maria Rita Passos-buenoAbstract:Among the heterogeneous group of autosomal recessive limb-girdle muscular dystrophies (AR LGMDs), the sarcoglycanopathies (LGMD2C-2F) represent a subgroup characterised by defects in the gamma, alpha, beta, and delta sarcoglycan genes, respectively. Genotype-phenotype correlations in these forms of AR LGMD are important to enhance our understanding of protein function. Regarding LGMD2F, only two homozygous frameshift mutations have been reported to date in patients with a severe phenotype. In the present report, through screening 23 unrelated AR LGMD patients, we identified three subjects with LGMD2F, two with a previously reported frameshift mutation and the other homozygous for a new missense mutation in the delta sarcoglycan gene. Interestingly, this new mutation is also associated with a severe clinical course. In addition, our results suggest that this form of severe AR LGMD is not very rare in our population.