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Carina Wallgren-pettersson - One of the best experts on this subject based on the ideXlab platform.
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Clinical utility gene card for: Nemaline Myopathy.
European journal of human genetics : EJHG, 2012Co-Authors: Kristen J. Nowak, Carina Wallgren-pettersson, Mark R. Davis, Phillipa J. Lamont, Nigel G. LaingAbstract:European Journal of Human Genetics (2012) 20, doi:10.1038/ejhg.2012.70; published online 18 April 20121. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Nemaline Myopathy (NEM1 – NEM7)Includes Nemaline Myopathy with excess thin filaments/actinaggregates; Nemaline Myopathy with cores; Nemaline Myopathy withintranuclear rods; and Amish Nemaline Myopathy.1.2 OMIM# of the diseaseNEM1 – 609284; NEM2 – 256030; NEM3 – 161800; NEM4 – 609285;NEM5 – 605355; NEM6 – 609273; NEM7 – 610687.1.3 Name of the analysed genes or DNA/chromosome segmentsSlow muscle a-tropomyosin (TPM3) – NEM1.Nebulin (NEB) – NEM2.Skeletal muscle a-actin (ACTA1) – NEM3.b-tropomyosin (TPM2) – NEM4.Slow muscle troponin-T (TNNT1) – NEM5.Kelch-repeat and BTB (POZ) Domain containing 13 (KBTBD13) –NEM6.Skeletal muscle cofilin (CFL2) – NEM7.1.4 OMIM# of the gene(s)TPM3¼*191030; NEB ¼*161650; ACTA1¼*102610; TPM2¼*190990; TNNT1¼*191041; KBTBD13¼*613727; CFL2 ¼*601443.1.5 Mutational spectrumTPM3Mainly dominant, missense mutations,
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Mutations in the β-tropomyosin (TPM2) gene – a rare cause of Nemaline Myopathy
Neuromuscular disorders : NMD, 2002Co-Authors: Kati Donner, Katarina Pelin, Hans H. Goebel, Miina Ollikainen, Maaret Ridanpää, Hans-jürgen Christen, Marianne De Visser, Carina Wallgren-petterssonAbstract:Abstract Nemaline Myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for α-actin and α-tropomyosin 3. A recessive mutation causing Nemaline Myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for Nemaline Myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the β-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.
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Clinical and genetic heterogeneity in autosomal recessive Nemaline Myopathy
Neuromuscular disorders : NMD, 1999Co-Authors: Carina Wallgren-pettersson, Katarina Pelin, Pirta Hilpelä, Kati Donner, Berardino Porfirio, Claudio Graziano, Kathryn J. Swoboda, Michel Fardeau, J. Andoni Urtizberea, Francesco MuntoniAbstract:Autosomal recessive Nemaline (rod) Myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive Nemaline Myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of Nemaline Myopathy. In four families with more severe forms of Nemaline Myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive Nemaline Myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.
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A gene for autosomal recessive Nemaline Myopathy assigned to chromosome 2q by linkage analysis
Neuromuscular disorders : NMD, 1995Co-Authors: Carina Wallgren-pettersson, Francesco Muntoni, Kristiina Avela, Sylvie Marchand, Juha Kolehmainen, Esa Tahvanainen, F. Juul Hansen, Victor Dubowitz, M. De Visser, I.m. Van LangenAbstract:Clinical genetic evidence suggests the existence of an autosomal recessive form of congenital Nemaline Myopathy in addition to the autosomal dominant one(s). One mutation in an Australian kindred has been identified as causing an autosomal dominant form of the disease. This mutation in the alpha-tropomyosin gene TPM3 has previously been excluded as causing autosomal recessive Nemaline Myopathy. We searched systematically for genetic linkage to autosomal recessive Nemaline Myopathy (NEM2) by studying microsatellite marker alleles in seven multiplex families from Finland, Denmark, Wales, England and The Netherlands. Significant evidence of linkage was found to markers of chromosome 2q, the highest multipoint lod score value being 5.34 for the marker D2S151. Recombinant genotypes in affected individuals demarcate the the region in which the NEM2 gene is likely to reside as a 13 cM region between the markers D2S150 and D2S142. These results confirm the existence of at least one distinctive form of autosomal recessive Nemaline Myopathy and provide a basis for the identification of its gene.
Katarina Pelin - One of the best experts on this subject based on the ideXlab platform.
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mutations in the nebulin gene as recessive Nemaline Myopathy
2016Co-Authors: Katarina Pelin, Alan H. Beggs, Pirta Hilpelä, Kati Donner, Stephen D Wiltont, Sylvie Odent, Nigel G Laingt, C Wallgrenpettersson, Patrick A Akkarit, Marielouise BangsAbstract:The congenital Nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of Nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of Nemaline Myopathy, the disease is caused by a mutation in the a-tropomyosin gene TPM3. The typical form of Nemaline Myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that muta- tions in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in
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Nemaline Myopathy caused by mutations in the nebulin gene may present as a distal Myopathy
Neuromuscular Disorders, 2011Co-Authors: Vilma-lotta Lehtokari, Agnes Herczegfalvi, Veronika Karcagi, Julien Pouget, Jerome Franques, Dominique Figarellabranger, Katarina Pelin, Maja Von Der Hagen, Jean-françois Pellissier, Angela HuebnerAbstract:Mutations in the nebulin gene are the main cause of autosomal recessive Nemaline Myopathy, with clinical presentations ranging from mild to severe disease. We have previously reported a nonspecific distal Myopathy caused by homozygous missense mutations in the nebulin gene in six Finnish patients from four different families. Here we describe three non-Finnish patients in two unrelated families with distal Nemaline Myopathy caused by four different compound heterozygous nebulin mutations, only one of which is a missense mutation. One of the mutations has previously been identified in one family with the severe form of Nemaline Myopathy. We conclude that Nemaline Myopathy and distal Myopathy caused by nebulin mutations form a clinical and histological continuum. Nemaline Myopathy should be considered as a differential diagnosis in patients presenting with an early-onset predominantly distal Myopathy.
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Magnetic resonance imaging of muscle in Nemaline Myopathy.
Neuromuscular disorders : NMD, 2004Co-Authors: Heinz Jungbluth, Nigel G. Laing, Kathryn N. North, Caroline Sewry, Serena J. Counsell, Joanna Allsop, Arijit Chattopadhyay, E. Mercuri, Graeme M. Bydder, Katarina PelinAbstract:We report muscle MRI findings of 10 patients from 8 families with Nemaline Myopathy. Patients with involvement of the nebulin (NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there was complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus. In moderate cases, there was predominant involvement of rectus femoris, vastus lateralis and hamstring muscles and diffuse involvement of anterior compartment and soleus. Patients with Nemaline Myopathy secondary to mutations in the skeletal muscle alpha-actin (ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii. Selective muscle involvement in both genetic categories was distinct from what has been reported in other congenital myopathies. We conclude that muscle MRI may be applied to distinguish Nemaline Myopathy from other conditions with similar clinical and histopathological features, to supplement clinical assessment in individual patients and to help direct genetic testing.
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mutations in the β tropomyosin tpm2 gene a rare cause of Nemaline Myopathy
Neuromuscular Disorders, 2002Co-Authors: Kati Donner, Katarina Pelin, Hans H. Goebel, Miina Ollikainen, Maaret Ridanpää, Hans-jürgen Christen, Marianne De Visser, C WallgrenpetterssonAbstract:Abstract Nemaline Myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for α-actin and α-tropomyosin 3. A recessive mutation causing Nemaline Myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for Nemaline Myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the β-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.
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Mutations in the β-tropomyosin (TPM2) gene – a rare cause of Nemaline Myopathy
Neuromuscular disorders : NMD, 2002Co-Authors: Kati Donner, Katarina Pelin, Hans H. Goebel, Miina Ollikainen, Maaret Ridanpää, Hans-jürgen Christen, Marianne De Visser, Carina Wallgren-petterssonAbstract:Abstract Nemaline Myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for α-actin and α-tropomyosin 3. A recessive mutation causing Nemaline Myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for Nemaline Myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the β-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.
James J. Dowling - One of the best experts on this subject based on the ideXlab platform.
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failure to identify modifiers of nebulin related Nemaline Myopathy in two pre clinical models of the disease
Biology Open, 2019Co-Authors: Julie Ruston, Henk Granzier, Monica J Justice, James J. DowlingAbstract:Nemaline Myopathy is a rare neuromuscular disorder that affects 1 in 50,000 live births, with prevalence as high as 1 in 20,000 in certain populations. 13 genes have been linked to Nemaline Myopathy, all of which are associated with the thin filament of the muscle sarcomere. Of the 13 associated genes, mutations in NEBULIN accounts for up to 50% of all cases. Currently, the disease is incompletely understood and there are no available therapeutics for patients. To address this urgent need for effective treatments for patients affected by NM, we conducted a large scale chemical screen in a zebrafish model of NEB related Nemaline Myopathy and a ENU based genetic screen in a mouse model of NEB exon 55 deletion, the most common NEBULIN mutation in Nemaline Myopathy patients. Neither screen was able to identify a candidate for therapy development, highlighting the need to transition from conventional chemical therapeutics to gene-based therapies for the treatment of Nemaline Myopathy.
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neb a zebrafish model of Nemaline Myopathy due to nebulin mutation
Disease Models & Mechanisms, 2012Co-Authors: William R Telfer, Darcee D Nelson, Trent Waugh, Susan V Brooks, James J. DowlingAbstract:SUMMARY Nemaline Myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with Nemaline Myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of Nemaline Myopathy. This model, termed neb , harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human Nemaline Myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of Nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of Nemaline Myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder.
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neb: a zebrafish model of Nemaline Myopathy due to nebulin mutation
Disease models & mechanisms, 2011Co-Authors: William R Telfer, Darcee D Nelson, Trent Waugh, Susan V Brooks, James J. DowlingAbstract:Nemaline Myopathy is one of the most common and severe non-dystrophic muscle diseases of childhood. Patients typically present in infancy with hypotonia, weakness, delayed motor development, and bulbar and respiratory difficulties. Mutations in six different genes are associated with Nemaline Myopathy, with nebulin mutations being the most common. No treatments or disease-modifying therapies have been identified for this disease. One of the major barriers to treatment development is the lack of models amenable to rapid and coordinated testing of potential therapeutic strategies. To overcome this barrier, we have characterized the first zebrafish model of Nemaline Myopathy. This model, termed neb, harbors a recessive mutation in the nebulin gene that results in decreased Nebulin protein levels, a severe motor phenotype and premature lethality. In addition to impaired motor function, neb zebrafish exhibit many of the features associated with human Nemaline Myopathy. These include impaired force generation, altered thin filament length and the presence of specific histopathological changes, including the formation of Nemaline bodies. In summary, neb zebrafish mirror the genetic, clinical and pathological aspects of Nemaline Myopathy due to NEB mutation, and thus are an excellent model for future therapy development for this devastating disorder.
Nigel G. Laing - One of the best experts on this subject based on the ideXlab platform.
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Clinical utility gene card for: Nemaline Myopathy.
European journal of human genetics : EJHG, 2012Co-Authors: Kristen J. Nowak, Carina Wallgren-pettersson, Mark R. Davis, Phillipa J. Lamont, Nigel G. LaingAbstract:European Journal of Human Genetics (2012) 20, doi:10.1038/ejhg.2012.70; published online 18 April 20121. DISEASE CHARACTERISTICS1.1 Name of the disease (synonyms)Nemaline Myopathy (NEM1 – NEM7)Includes Nemaline Myopathy with excess thin filaments/actinaggregates; Nemaline Myopathy with cores; Nemaline Myopathy withintranuclear rods; and Amish Nemaline Myopathy.1.2 OMIM# of the diseaseNEM1 – 609284; NEM2 – 256030; NEM3 – 161800; NEM4 – 609285;NEM5 – 605355; NEM6 – 609273; NEM7 – 610687.1.3 Name of the analysed genes or DNA/chromosome segmentsSlow muscle a-tropomyosin (TPM3) – NEM1.Nebulin (NEB) – NEM2.Skeletal muscle a-actin (ACTA1) – NEM3.b-tropomyosin (TPM2) – NEM4.Slow muscle troponin-T (TNNT1) – NEM5.Kelch-repeat and BTB (POZ) Domain containing 13 (KBTBD13) –NEM6.Skeletal muscle cofilin (CFL2) – NEM7.1.4 OMIM# of the gene(s)TPM3¼*191030; NEB ¼*161650; ACTA1¼*102610; TPM2¼*190990; TNNT1¼*191041; KBTBD13¼*613727; CFL2 ¼*601443.1.5 Mutational spectrumTPM3Mainly dominant, missense mutations,
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Variable presentation of Nemaline Myopathy: novel mutation of alpha actin gene.
Muscle & nerve, 2007Co-Authors: Anthony Bouldin, Kathleen Patterson, Melissa A Parisi, Nigel G. Laing, Sidney M GospeAbstract:Nemaline Myopathy is a rare disorder of varying severity and genetic etiology. We present two cases, a father and son, with a novel missense mutation in the alpha actin gene. Both have a history of early motor impairment, with the son's course being considerably more severe. This pair illustrates the clinical variability of Nemaline Myopathy, highlighting the possible influence of environmental and epigenetic factors. Implications for the current classification system and prognosis are discussed.
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Magnetic resonance imaging of muscle in Nemaline Myopathy.
Neuromuscular disorders : NMD, 2004Co-Authors: Heinz Jungbluth, Nigel G. Laing, Kathryn N. North, Caroline Sewry, Serena J. Counsell, Joanna Allsop, Arijit Chattopadhyay, E. Mercuri, Graeme M. Bydder, Katarina PelinAbstract:We report muscle MRI findings of 10 patients from 8 families with Nemaline Myopathy. Patients with involvement of the nebulin (NEB) gene showed a consistent pattern of selective muscle involvement corresponding to clinical severity. In mild cases, there was complete sparing of thigh muscles and selective involvement of tibialis anterior and soleus. In moderate cases, there was predominant involvement of rectus femoris, vastus lateralis and hamstring muscles and diffuse involvement of anterior compartment and soleus. Patients with Nemaline Myopathy secondary to mutations in the skeletal muscle alpha-actin (ACTA1) gene showed diffuse involvement of thigh and leg muscles with relative sparing of the gastrocnemii. Selective muscle involvement in both genetic categories was distinct from what has been reported in other congenital myopathies. We conclude that muscle MRI may be applied to distinguish Nemaline Myopathy from other conditions with similar clinical and histopathological features, to supplement clinical assessment in individual patients and to help direct genetic testing.
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An αtropomyosin mutation alters dimer preference in Nemaline Myopathy
Annals of neurology, 2004Co-Authors: Mark A. Corbett, Nigel G. Laing, Kathryn N. North, P. Anthony Akkari, Ana Domazetovska, Sandra T. Cooper, Peter W. Gunning, Edna C. HardemanAbstract:Nemaline Myopathy is a human neuromuscular disorder associated with muscle weakness, Z-line accumulations (rods), and myofibrillar disorganization. Disease-causing mutations have been identified in genes encoding muscle thin filament proteins: actin, nebulin, slow troponin T, βTropomyosin, and αTropomyosinslow. Skeletal muscle expresses three tropomyosin (Tm) isoforms from separate genes: αTmfast(αTm, TPM1), βTm (TPM2), and αTmslow (γTm, TPM3). In this article, we show that the level of βTm, but not αTmfast protein, is reduced in human patients with mutations in αTmslow and in a transgenic mouse model of αTmslow(Met9Arg) Nemaline Myopathy. A postnatal time course of Tm expression in muscles of the mice indicated that the onset of αTmslow(Met9Arg) expression coincides with the decline of βTm. Reduction of βTm levels is independent of the degree of pathology (rods) within a muscle and is detected before the onset of muscle weakness. Thus, reduction in the level of βTm represents an early clinical diagnostic marker for αTmslow-based mutations. Examinations of tropomyosin dimer formation using either recombinant proteins or sarcomeric extracts show that the mutation reduces the formation of the preferred α/β heterodimer. We suggest this perturbation of tropomyosin isoform levels and dimer preference alters sarcomeric thin filament dynamics and contributes to muscle weakness in Nemaline Myopathy. Ann Neurol 2004
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Nemaline Myopathy a clinical study of 143 cases
Annals of Neurology, 2001Co-Authors: Nigel G. Laing, Monique M. Ryan, Susan T. Iannaccone, Alan H. Beggs, Corinne D. Strickland, Christina Schnell, Lloyd K. Shield, Graeme Morgan, Kathryn N. NorthAbstract:We report 143 Australian and North American cases of primary Nemaline Myopathy. As classified by the European Neuromuscular Centre guidelines, 23 patients had severe congenital, 29 intermediate congenital, 66 typical congenital, 19 childhood-onset, and 6 adult-onset Nemaline Myopathy. Inheritance was autosomal recessive in 29 patients, autosomal dominant in 41, sporadic in 72, and indeterminate in 1. Twenty-two patients had skeletal muscle actin mutations and 4 had mutations in the alpha-tropomyosin(slow) gene. Obstetric complications occurred in 49 cases. Seventy-five patients had significant respiratory disease during the first year of life, and 79 had feeding difficulties. Atypical features in a minority of cases included arthrogryposis, central nervous system involvement, and congenital fractures. Progressive distal weakness developed in a minority of patients. Thirty patients died, the majority during the first 12 months of life. All deaths were due to respiratory insufficiency, which was frequently underrecognized in older patients. Arthrogryposis, neonatal respiratory failure, and failure to achieve early motor milestones were associated with early mortality. Morbidity from respiratory tract infections and feeding difficulties frequently diminished with increasing age. Aggressive early management is warranted in most cases of congenital Nemaline Myopathy.
Kati Donner - One of the best experts on this subject based on the ideXlab platform.
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mutations in the nebulin gene as recessive Nemaline Myopathy
2016Co-Authors: Katarina Pelin, Alan H. Beggs, Pirta Hilpelä, Kati Donner, Stephen D Wiltont, Sylvie Odent, Nigel G Laingt, C Wallgrenpettersson, Patrick A Akkarit, Marielouise BangsAbstract:The congenital Nemaline myopathies are rare hereditary muscle disorders characterized by the presence in the muscle fibers of Nemaline bodies consisting of proteins derived from the Z disc and thin filament. In a single large Australian family with an autosomal dominant form of Nemaline Myopathy, the disease is caused by a mutation in the a-tropomyosin gene TPM3. The typical form of Nemaline Myopathy is inherited as an autosomal recessive trait, the locus of which we previously assigned to chromosome 2q21.2-q22. We show here that muta- tions in the nebulin gene located within this region are associated with the disease. The nebulin protein is a giant protein found in
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mutations in the β tropomyosin tpm2 gene a rare cause of Nemaline Myopathy
Neuromuscular Disorders, 2002Co-Authors: Kati Donner, Katarina Pelin, Hans H. Goebel, Miina Ollikainen, Maaret Ridanpää, Hans-jürgen Christen, Marianne De Visser, C WallgrenpetterssonAbstract:Abstract Nemaline Myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for α-actin and α-tropomyosin 3. A recessive mutation causing Nemaline Myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for Nemaline Myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the β-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.
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Mutations in the β-tropomyosin (TPM2) gene – a rare cause of Nemaline Myopathy
Neuromuscular disorders : NMD, 2002Co-Authors: Kati Donner, Katarina Pelin, Hans H. Goebel, Miina Ollikainen, Maaret Ridanpää, Hans-jürgen Christen, Marianne De Visser, Carina Wallgren-petterssonAbstract:Abstract Nemaline Myopathy is a clinically and genetically heterogeneous muscle disorder. In the nebulin gene we have detected a number of autosomal recessive mutations. Both autosomal dominant and recessive mutations have been detected in the genes for α-actin and α-tropomyosin 3. A recessive mutation causing Nemaline Myopathy among the Old Order Amish has recently been identified in the gene for slow skeletal muscle troponin T. As linkage studies had shown that at least one further gene exists for Nemaline Myopathy, we investigated another tropomyosin gene expressed in skeletal muscle, the β-tropomyosin 2 gene. Screening 66 unrelated patients, using single strand conformation polymorphism analysis and sequencing, we found four polymorphisms and two heterozygous missense mutations. Both mutations affect conserved amino acids, and in both cases, the mutant allele is expressed. We speculate that the observed mutations affect the formation of the tropomyosin dimer and its actin-binding properties.
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Clinical and genetic heterogeneity in autosomal recessive Nemaline Myopathy
Neuromuscular disorders : NMD, 1999Co-Authors: Carina Wallgren-pettersson, Katarina Pelin, Pirta Hilpelä, Kati Donner, Berardino Porfirio, Claudio Graziano, Kathryn J. Swoboda, Michel Fardeau, J. Andoni Urtizberea, Francesco MuntoniAbstract:Autosomal recessive Nemaline (rod) Myopathy is clinically and genetically heterogeneous. A clinically distinct, typical form, with onset in infancy and a non-progressive or slowly progressive course, has been assigned to a region on chromosome 2q22 harbouring the nebulin gene Mutations have now been found in this gene, confirming its causative role. The gene for slow tropomyosin TPM3 on chromosome 1q21, previously found to cause a dominantly inherited form, has recently been found to be homozygously mutated in one severe consanguineous case. Here we wished to determine the degree of genetic homogeneity or heterogeneity of autosomal recessive Nemaline Myopathy by linkage analysis of 45 families from 10 countries. Forty-one of the families showed linkage results compatible with linkage to markers in the nebulin region, the highest combined lod scores at zero recombination being 14.13 for the marker D2S2236. We found no indication of genetic heterogeneity for the typical form of Nemaline Myopathy. In four families with more severe forms of Nemaline Myopathy, however, linkage to both the nebulin and the TPM3 locus was excluded. Our results indicate that at least three genetic loci exist for autosomal recessive Nemaline Myopathy. Studies of additional families are needed to localise the as yet unknown causative genes, and to fully elucidate genotype-phenotype correlations.
