RESUMEN
AIMS: Mutations of the LMNA gene encoding lamin A/C induce heterogeneous phenotypes ranging from cardiopathies and myopathies to lipodystrophies. The aim of this study was to compare cardiometabolic complications in patients with heterozygous LMNA mutations at the 482nd codon, the 'hotspot' for partial lipodystrophy, with carriers of other, non-R482 LMNA mutations. METHODS AND RESULTS: This study included 29 patients with R482 LMNA mutations, 29 carriers of non-R482 LMNA mutation and 19 control subjects. Cardiac and metabolic phenotypes were compared between groups. A family history of either cardiac implantable electronic devices (CIEDs; P < 0.001) or sudden death (P < 0.01) was more frequent in non-R482 than R482 carriers. The non-R482 carriers also had more abnormalities on electrocardiography and received CIEDs more often than R482 carriers (P < 0.001). On cardiac ultrasound, non-R482 patients had greater frequencies of left atrial enlargement (P < 0.05) and lower left ventricular ejection fractions (P < 0.01) than R482 carriers. In contrast, R482 carriers had lower BMI (P < 0.05), leptin (P < 0.01) and fat mass (P < 0.001), but higher intra-/total abdominal fat-mass ratios (P < 0.001) and prevalences of diabetes (P < 0.01) and hypertriglyceridaemia (P < 0.05) than non-R482 carriers, with a trend towards more coronary artery disease. However, non-R482 carriers had higher intra-/total abdominal fat-mass ratios (P < 0.02) and prevalences of diabetes (P < 0.001) and hypertriglyceridaemia (P < 0.05) than the controls. CONCLUSION: Non-R482 carriers present more frequently with arrhythmias than R482 carriers, who twice as often have diabetes, suggesting that follow-up for laminopathies could be adjusted for genotype. Non-R482 mutations require ultra-specialized cardiac follow-up, and coronary artery disease should not be overlooked. Although overlapping phenotypes are found, LMNA mutations essentially lead to tissue-specific diseases, favouring genotype-specific pathophysiological mechanisms.
Asunto(s)
Enfermedades Cardiovasculares/genética , Lamina Tipo A/genética , Enfermedades Metabólicas/genética , Mutación , Adulto , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/epidemiología , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Frecuencia de los Genes , Estudios de Asociación Genética , Predisposición Genética a la Enfermedad , Genotipo , Heterocigoto , Humanos , Lipodistrofia/complicaciones , Lipodistrofia/diagnóstico , Lipodistrofia/epidemiología , Lipodistrofia/genética , Lipodistrofia Parcial Familiar/complicaciones , Lipodistrofia Parcial Familiar/epidemiología , Lipodistrofia Parcial Familiar/genética , Estudios Longitudinales , Masculino , Enfermedades Metabólicas/diagnóstico , Enfermedades Metabólicas/epidemiología , Persona de Mediana Edad , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND AND PURPOSE: The aim was to determine the genetic background of unknown muscular dystrophy in five French families. METHODS: Twelve patients with limb girdle muscular dystrophy or distal myopathy were clinically evaluated. Gene mutations were identified using targeted exon sequencing and mutated DNAJB6 was tested in vitro. RESULTS: Five patients presented with distal lower limb weakness whilst others had proximal presentation with a variable rate of progression starting at the mean age of 38.5 years. Two novel mutations (c.284A>T, p.Asn95Ile, two families; and c.293_295delATG, p.Asp98del, one family) as well as the previously reported c.279C>G (p.Phe93Leu, two families) mutation in DNAJB6 were identified. All showed a reduced capacity to prevent protein aggregation. CONCLUSIONS: The mutational and phenotypical spectrum of DNAJB6-caused muscle disease is larger than previously reported, including also dysphagia. The originally reported c.279C>G (p.Phe93Leu) mutation is now identified in four different populations and appears to be a mutational hotspot. Our report confirms that some DNAJB6 mutations cause distal-onset myopathy and hence DNAJB6 defects should be considered broadly in dominant muscular dystrophy families.
Asunto(s)
Miopatías Distales/genética , Proteínas del Choque Térmico HSP40/genética , Chaperonas Moleculares/genética , Distrofia Muscular de Cinturas/genética , Mutación , Proteínas del Tejido Nervioso/genética , Adulto , Anciano , Anciano de 80 o más Años , Progresión de la Enfermedad , Femenino , Francia , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/genética , Linaje , FenotipoRESUMEN
Myofibrillar myopathies (MFM) are mostly adult-onset diseases characterized by progressive morphological alterations of the muscle fibers beginning in the Z-disk and the presence of protein aggregates in the sarcoplasm. They are mostly caused by mutations in different genes that encode Z-disk proteins, including DES, CRYAB, LDB3, MYOT, FLNC and BAG3. A large family of French origin, presenting an autosomal dominant pattern, characterized by cardiac arrhythmia associated to late-onset muscle weakness, was evaluated to clarify clinical, morphological and genetic diagnosis. Muscle weakness began during adult life (over 30 years of age), and had a proximal distribution. Histology showed clear signs of a myofibrillar myopathy, but with unusual, large inclusions. Subsequently, genetic testing was performed in MFM genes available for screening at the time of clinical/histological diagnosis, and desmin (DES), αB-crystallin (CRYAB), myotilin (MYOT) and ZASP (LDB3), were excluded. LMNA gene screening found the p.R296C variant which did not co-segregate with the disease. Genome wide scan revealed linkage to 7q.32, containing the FLNC gene. FLNC direct sequencing revealed a heterozygous c.3646T>A p.Tyr1216Asn change, co-segregating with the disease, in a highly conserved amino acid of the protein. Normal filamin C levels were detected by Western-blot analysis in patient muscle biopsies and expression of the mutant protein in NIH3T3 showed filamin C aggregates. This is an original FLNC mutation in a MFM family with an atypical clinical and histopathological presentation, given the presence of significantly focal lesions and prominent sarcoplasmic masses in muscle biopsies and the constant heart involvement preceding significantly the onset of the myopathy. Though a rare etiology, FLNC gene should not be excluded in early-onset arrhythmia, even in the absence of myopathy, which occurs later in the disease course.
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Arritmias Cardíacas/etiología , Filaminas/genética , Debilidad Muscular/etiología , Enfermedades Musculares/complicaciones , Enfermedades Musculares/genética , Mutación Missense/genética , Adolescente , Adulto , Edad de Inicio , Anciano , Secuencia de Aminoácidos , Análisis Mutacional de ADN , Familia , Femenino , Genoma Humano , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Miofibrillas/patología , Linaje , Adulto JovenRESUMEN
Myofibrillar myopathies (MFM) have been described in the mid-1990s as a group of diseases sharing common histological features, including an abnormal accumulation of intrasarcoplasmic proteins, the presence of vacuoles and a disorganization of the intermyofibrillar network beginning at the Z-disk. The boundaries of this concept are still uncertain, and whereas six genes (DES, CRYAB, LDB3/ZASP, MYOT, FLNC and BAG3) are now classically considered as responsible for MFM, other entities such as FHL1 myopathy or Hereditary Myopathy with Early Respiratory Failure linked to mutations of titin can now as well be included in this group. The diagnosis of MFM is not always easy; as histological lesions can be focal, and muscle biopsy may be disappointing; this has led to a growing importance of muscle imaging, and the selectivity of muscle involvement has now been described in several disorders. Due to the rarity of these myopathies, if some clinical patterns (such as distal myopathy associated with cardiomyopathy due to desmin mutations) are now well known, surprises remain possible and should lead to systematic testing of the known genes in case of a typical histological presentation. In this paper, we aim at reviewing the data acquired on the six main genes listed above as well as presenting the experience from two French reference centres, Paris and Marseilles.
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Miofibrillas/patología , Miopatías Estructurales Congénitas/patología , Adolescente , Adulto , Niño , Femenino , Humanos , Masculino , Persona de Mediana Edad , Proteínas Musculares/genética , Músculo Esquelético/patología , Miofibrillas/genética , Miopatías Estructurales Congénitas/genética , Miopatías Estructurales Congénitas/terapia , Adulto JovenRESUMEN
Autosomal dominant Emery-Dreifuss muscular dystrophy is caused by mutations in LMNA gene encoding lamins A and C. The disease is characterized by early onset joint contractures during childhood associated with humero-peroneal muscular wasting and weakness, and by the development of a cardiac disease in adulthood. Important intra-familial variability characterized by a wide range of age at onset of myopathic symptoms (AOMS) has been recurrently reported, suggesting the contribution of a modifier gene. Our objective was to identify a modifier locus of AOMS in relation with the LMNA mutation. To map the modifier locus, we genotyped 291 microsatellite markers in 59 individuals of a large French family, where 19 patients carrying the same LMNA mutation, exhibited wide range of AOMS. We performed Bayesian Markov Chain Monte Carlo-based joint segregation and linkage methods implemented in the Loki software, and detected a strong linkage signal on chromosome 2 between markers D2S143 and D2S2244 (211 cM) with a Bayes factor of 28.7 (empirical p value = 0.0032). The linked region harbours two main candidate genes, DES and MYL1 encoding desmin and light chain of myosin. Importantly, the impact of the genotype on the phenotype for this locus showed an overdominant effect with AOMS 2 years earlier for the homozygotes of the rare allele and 37 years earlier for the heterozygotes than the homozygotes for the common allele. These results provide important highlights for the natural history and for the physiopathology of Emery-Dreifuss muscular dystrophy.
Asunto(s)
Músculo Esquelético/fisiopatología , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Edad de Inicio , Teorema de Bayes , Femenino , Predisposición Genética a la Enfermedad , Humanos , Lamina Tipo A/genética , Masculino , Repeticiones de Microsatélite , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/epidemiología , Distrofia Muscular de Emery-Dreifuss/patología , LinajeRESUMEN
Bethlem myopathy and Ullrich congenital muscular dystrophy are part of the heterogeneous group of collagen VI-related muscle disorders. They are caused by mutations in collagen VI (ColVI) genes (COL6A1, COL6A2, and COL6A3) while LMNA mutations cause autosomal dominant Emery-Dreifuss muscular dystrophy. A muscular dystrophy pattern and contractures are found in all three conditions, making differential diagnosis difficult especially in young patients when cardiomyopathy is absent. We retrospectively assessed upper and lower limb muscle CT scans in 14 Bethlem/Ullrich patients and 13 Emery-Dreifuss patients with identified mutations. CT was able to differentiate Emery-Dreifuss muscular dystrophy from ColVI-related myopathies in selected thigh muscles and to a lesser extent calves muscles: rectus femoris fatty infiltration was selectively present in Bethlem/Ullrich patients while posterior thigh muscles infiltration was more prominently found in Emery-Dreifuss patients. A more severe fatty infiltration particularly in the leg posterior compartment was found in the Emery-Dreifuss group.
Asunto(s)
Enfermedades del Colágeno/diagnóstico por imagen , Colágeno Tipo VI , Distrofia Muscular de Emery-Dreifuss/diagnóstico por imagen , Tejido Adiposo/diagnóstico por imagen , Adolescente , Adulto , Edad de Inicio , Enfermedades del Colágeno/genética , Colágeno Tipo VI/genética , ADN/genética , Diagnóstico Diferencial , Femenino , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/genética , Mutación/genética , Estudios Retrospectivos , Tomografía Computarizada por Rayos X , Adulto JovenRESUMEN
BACKGROUND: Heart-hand syndromes are a heterogeneous group of genetic disorders characterised by the association of congenital cardiac disease and limb deformities. Laminopathies are a group of diseases caused by mutations in the LMNA gene encoding A-type lamins. RESULTS: We report a new LMNA mutation (c.1609-12T>G, IVS9-12 T>G) that creates a new cryptic splicing site with the retention of 11 intronic nucleotides in the mRNA. This LMNA mutation segregates with a new type of heart-hand syndrome in a previously reported family suffering from adult onset progressive conduction system disease, atrial and ventricular tachyarrhythmias, sudden death, dilated cardiomyopathy, and brachydactyly with predominant foot involvement. Analysis of the fibroblasts of two affected family members identified for the first time a truncated lamin A/C protein resulting from the frame shift created by the new splicing site, together with nuclear envelope abnormalities confirming that this LMNA mutation is pathogenic. CONCLUSIONS: This new heart-hand syndrome should therefore be considered as a new kind of laminopathy. As part of laminopathies with heart involvement, patients presenting with this phenotype and their relatives are at risk for developing sudden cardiac death and should beneficiate from appropriate LMNA genetic diagnosis.
Asunto(s)
Cardiopatías Congénitas/genética , Lamina Tipo A/genética , Deformidades Congénitas de las Extremidades/genética , Adulto , Anciano , Femenino , Mutación del Sistema de Lectura , Cardiopatías Congénitas/complicaciones , Heterocigoto , Humanos , Deformidades Congénitas de las Extremidades/complicaciones , Masculino , Persona de Mediana Edad , Linaje , Sitios de Empalme de ARN , ARN Mensajero/químicaRESUMEN
BACKGROUND: Mutations in the EMD and LMNA genes, encoding emerin and lamins A and C, are responsible for the X-linked and autosomal dominant and recessive forms of Emery-Dreifuss muscular dystrophy (EDMD). LMNA mutations can also lead to several other disorders, collectively termed laminopathies, involving heart, fat, nerve, bone, and skin tissues, and some premature ageing syndromes. METHODS: Fourteen members of a single family underwent neurologic, electromyographic, and cardiologic assessment. Gene mutation and protein expression analyses were performed for lamins A/C and emerin. RESULTS: Clinical investigations showed various phenotypes, including isolated cardiac disease (seven patients), axonal neuropathy (one patient), and a combination of EDMD with axonal neuropathy (two patients), whereas five subjects remained asymptomatic. Genetic analyses identified the coincidence of a previously described homozygous LMNA mutation (c.892C-->T, p. R298C) and a new in-frame EMD deletion (c.110-112delAGA, p. delK37), which segregate independently. Analyses of the contribution of these mutations showed 1) the EMD codon deletion acts in X-linked dominant fashion and was sufficient to induce the cardiac disease, 2) the combination of both the hemizygous EMD and the homozygous LMNA mutations was necessary to induce the EDMD phenotype, 3) emerin was present in reduced amount in EMD-mutated cells, and 4) lamin A/C and emerin expression was most dramatically affected in the doubly mutated fibroblasts. CONCLUSIONS: This highlights the crucial role of lamin A/C-emerin interactions, with evidence for synergistic effects of these mutations that lead to Emery-Dreifuss muscular dystrophy as the worsened result of digenic mechanism in this family.
Asunto(s)
Lamina Tipo A/genética , Proteínas de la Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Proteínas Nucleares/genética , Adolescente , Adulto , Western Blotting , Electromiografía , Femenino , Fibroblastos/metabolismo , Técnica del Anticuerpo Fluorescente , Genotipo , Cardiopatías/genética , Humanos , Lamina Tipo A/metabolismo , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Distrofia Muscular de Emery-Dreifuss/patología , Mutación , Proteínas Nucleares/metabolismo , Linaje , Enfermedades del Sistema Nervioso Periférico/genética , Fenotipo , Reacción en Cadena de la PolimerasaRESUMEN
BACKGROUND: Mutations in the LMNA gene, encoding human lamin A/C, have been associated with an increasing number of disorders often involving skeletal and cardiac muscle, but no clear genotype/phenotype correlation could be established to date. METHODS: We analyzed the LMNA gene in a large cohort of patients mainly affected by neuromuscular or cardiac disease and clustered mutated patients in two groups to unravel possible correlations. RESULTS: We identified 28 variants, 9 of which reported for the first time. The two groups of patients were characterized by clinical and genetic differences: 1) patients with childhood onset displayed skeletal muscle involvement with predominant scapuloperoneal and facial weakness associated with missense mutations; 2) patients with adult onset mainly showed cardiac disorders or myopathy with limb girdle distribution, often associated with frameshift mutations presumably leading to a truncated protein. CONCLUSIONS: Our findings, supported by meta-analysis of previous literature, suggest the presence of two different pathogenetic mechanisms: late onset phenotypes may arise through loss of function secondary to haploinsufficiency, while dominant negative or toxic gain of function mechanisms may explain the severity of early phenotypes. This model of patient stratification may help patient management and facilitate future studies aimed at deciphering lamin A/C pathogenesis.
Asunto(s)
Predisposición Genética a la Enfermedad/genética , Cardiopatías/genética , Laminas/genética , Mutación/genética , Enfermedades Neuromusculares/genética , Adulto , Edad de Inicio , Niño , Preescolar , Análisis por Conglomerados , Estudios de Cohortes , Análisis Mutacional de ADN , Progresión de la Enfermedad , Mutación del Sistema de Lectura/genética , Marcadores Genéticos/genética , Haplotipos/genética , Cardiopatías/metabolismo , Cardiopatías/fisiopatología , Humanos , Lamina Tipo A/genética , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Mutación Missense/genética , Miocardio/metabolismo , Miocardio/patología , Enfermedades Neuromusculares/metabolismo , Enfermedades Neuromusculares/fisiopatología , FenotipoRESUMEN
The LMNA gene encodes lamins A and C, components of the nuclear envelope. Its mutations cause a wide range of diseases named laminopathies involving either specific tissues in isolated fashion (cardiac and skeletal muscles, peripheral nerve, adipose tissue) or several tissues in a generalized way (premature ageing syndromes and related disorders). The striated muscle laminopathies include a variety of well clinically characterized disorders where cardiac muscle involvement represents the common feature that coexists with or without skeletal muscle disease. The cardiac disease of LMNA mutated patients is classically defined by conduction system and rhythm disturbances occurring early in the course of the disease, followed by dilated cardiomyopathy and heart failure. These features are life threatening and often responsible of cardiac sudden death. When associated, the skeletal muscle involvement is characterized by muscle weakness and wasting of variable topography with or without early joint contractures and spinal rigidity. Specific management of the cardiac disease to includes antiarrhythmic drugs, cardiac devices such as implantable cardioverter for primary and secondary prevention of sudden death, and heart transplantation at the end stage of heart failure. A large number of LMNA mutations leading to striated muscle laminopathies have been reported without so far any clear and definite phenotype/genotype relation. Finally, among the diverse hypotheses for pathomechanisms of LMNA mutations, the structural hypothesis suggesting a defective role of lamins A/C in maintaining the structural integrity of the nuclear envelope in striated muscles under constant mechanical stress is highly attractive to link the LMNA mutations and the cardiac disease.
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Cardiopatías/genética , Lamina Tipo A/genética , Sistema de Conducción Cardíaco/fisiopatología , Cardiopatías/fisiopatología , Humanos , Lipodistrofia/genética , Distrofias Musculares/genética , MutaciónRESUMEN
It has been demonstrated that nuclear lamins are important proteins in maintaining cellular as well as nuclear integrity, and in maintaining chromatin organization in the nucleus. Moreover, there is growing evidence that lamins play a prominent role in transcriptional control. The family of laminopathies is a fast-growing group of diseases caused by abnormalities in the structure or processing of the lamin A/C (LMNA) gene. Mutations or incorrect processing cause more than a dozen different inherited diseases, ranging from striated muscular diseases, via fat- and peripheral nerve cell diseases, to progeria. This broad spectrum of diseases can only be explained if the responsible A-type lamin proteins perform multiple functions in normal cells. This review gives an overview of current knowledge on lamin structure and function and all known diseases associated with LMNA abnormalities. Based on the knowledge of the different functions of A-type lamins and associated proteins, explanations for the observed phenotypes are postulated. It is concluded that lamins seem to be key players in, among others, controlling the process of cellular ageing, since disturbance in lamin protein structure gives rise to several forms of premature ageing.
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Envejecimiento Prematuro/patología , Envejecimiento Prematuro/fisiopatología , Laminas/fisiología , Lámina Nuclear/patología , HumanosRESUMEN
Individuals with the same genetic disorder often show remarkable differences in clinical severity, a finding generally attributed to the genetic background. We identified two patients with genetically proven Emery-Dreifuss muscular dystrophy (EDMD) who followed an unusual course and had uncommon clinicopathological findings. We hypothesized digenic inheritance and looked for additional molecular explanations. Mutations in additional separate genes were identified in both patients. The first patient was a member of a family with molecularly proven X-linked EDMD. However, the clinical features were unusually severe for this condition in the propositus: he presented at 2.5 years with severe proximal weakness and markedly elevated serum creatine kinase. Muscle weakness rapidly progressed, leading to loss of independent ambulation by the age of 12. In addition, the patient developed cardiac conduction system disease requiring pacing at the age of 11 and severe dilated cardiomyopathy in the early teens. Despite pacing, he had several syncopal episodes attributed to ventricular dysrhythmias. As these resemble the cardiac features of patients with the autosomal dominant variant of EDMD, we examined the lamin A/C gene, identifying a de-novo mutation in the propositus. The second patient had a cardioskeletal myopathy, similar to his mother who had died more than 20 years previously. Because of the dominant family history, a laminopathy was suspected and a mutation in exon 11 of the LMNA gene was identified. This mutation, however, was not present in his mother, but instead, surprisingly, was identified in his virtually asymptomatic father. Unusual accumulations of desmin found in the cardiac muscle of the propositus prompted us to examine the desmin gene in this patient, and in so doing, we identified a desmin mutation, in addition to the LMNA mutation in the propositus. These cases suggest that separate mutations in related proteins that are believed to interact, or that represent different parts of a presumed functional pathway, may synergistically contribute to disease severity in autosomal dominant EDMD. Furthermore, digenic inheritance may well contribute to the clinical severity of many other neuromuscular disorders.
Asunto(s)
Desmina/genética , Proteínas de la Membrana/genética , Distrofia Muscular de Emery-Dreifuss/genética , Mutación , Timopoyetinas/genética , Adolescente , Adulto , Cardiomiopatía Dilatada/genética , Cardiomiopatía Dilatada/patología , Preescolar , Desmina/metabolismo , Femenino , Humanos , Laminina/genética , Laminina/metabolismo , Imagen por Resonancia Magnética , Masculino , Proteínas de la Membrana/metabolismo , Persona de Mediana Edad , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Distrofia Muscular de Emery-Dreifuss/patología , Miocardio/metabolismo , Miocardio/ultraestructura , Proteínas Nucleares , Linaje , Timopoyetinas/metabolismoRESUMEN
Dropped head syndrome is characterized by severe weakness of neck extensor muscles with sparing of the flexors. It is a prominent sign in several neuromuscular conditions, but it may also be an isolated feature with uncertain aetiology. We report two children in whom prominent weakness of neck extensor muscles is associated with mutations in lamin A/C (LMNA) and selenoprotein N1 (SEPN1) genes, respectively. This report expands the underlying causes of the dropped head syndrome which may be the presenting feature of a congenital muscular dystrophy.
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Laminas/genética , Proteínas Musculares/genética , Distrofias Musculares/genética , Distrofias Musculares/fisiopatología , Mutación , Arginina/genética , Niño , Análisis Mutacional de ADN/métodos , Femenino , Glicina/genética , Humanos , Lactante , Lamina Tipo A , Masculino , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Músculos del Cuello/patología , Músculos del Cuello/fisiopatología , Selenoproteínas , SíndromeRESUMEN
BACKGROUND: Skeletal muscle disorders associated with mutations of lamin A/C gene include autosomal Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B. The pathogenic mechanism underlying these diseases is unknown. Recent data suggest an impairment of signalling mechanisms as a possible cause of muscle malfunction. A molecular complex in muscle cells formed by lamin A/C, emerin, and nuclear actin has been identified. The stability of this protein complex appears to be related to phosphorylation mechanisms. OBJECTIVE: To analyse lamin A/C phosphorylation in control and laminopathic muscle cells. METHODS: Lamin A/C N-terminal phosphorylation was determined in cultured mouse myoblasts using a specific antibody. Insulin treatment of serum starved myoblast cultures was carried out to evaluate involvement of insulin signalling in the phosphorylation pathway. Screening of four Emery-Dreifuss and one limb girdle muscular dystrophy 1B cases was undertaken to investigate lamin A/C phosphorylation in both cultured myoblasts and mature muscle fibres. RESULTS: Phosphorylation of lamin A was observed during myoblast differentiation or proliferation, along with reduced lamin A/C phosphorylation in quiescent myoblasts. Lamin A N-terminus phosphorylation was induced by an insulin stimulus, which conversely did not affect lamin C phosphorylation. Lamin A/C was also hyperphosphorylated in mature muscle, mostly in regenerating fibres. Lamin A/C phosphorylation was strikingly reduced in laminopathic myoblasts and muscle fibres, while it was preserved in interstitial fibroblasts. CONCLUSIONS: Altered lamin A/C interplay with a muscle specific phosphorylation partner might be involved in the pathogenic mechanism of Emery-Dreifuss muscular dystrophy and limb girdle muscular dystrophy 1B.
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Lamina Tipo A/metabolismo , Distrofia Muscular de Emery-Dreifuss/metabolismo , Mioblastos/metabolismo , Procesamiento Proteico-Postraduccional , Animales , Diferenciación Celular , Línea Celular , Humanos , Insulina/metabolismo , Lamina Tipo A/genética , Ratones , Fibras Musculares Esqueléticas/metabolismo , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Distrofia Muscular de Emery-Dreifuss/genética , Fosforilación , Transducción de SeñalRESUMEN
Mutations of the LMNA gene, encoding the nuclear envelope proteins lamins A and C, give rise to Emery-Dreifuss muscular dystrophy and to limb-girdle muscular dystrophy 1B (EDMD and LGMD1B). With one exception, all the reported EDMD and LGMD1B mutations are confined to the first 10 exons of the gene. We report four separate cases, with mutations in the same codon of LMNA exon 11, characterized by remarkable variability of clinical findings, in addition to features not previously reported. One patient had congenital weakness and died in early childhood. In two other patients, severe cardiac problems arose early and, in one of these, cardiac signs preceded by many years the onset of skeletal muscle weakness. The fourth case had a mild and late-onset LGMD1B phenotype. Our cases further expand the clinical spectrum associated with mutations in the LMNA gene and provide new evidence of the role played by the C-terminal domain of lamin A.
Asunto(s)
Lamina Tipo A/genética , Músculo Esquelético/fisiopatología , Enfermedades Musculares/genética , Enfermedades Musculares/fisiopatología , Miocardio/patología , Adulto , Sustitución de Aminoácidos/genética , Arginina/genética , Cardiomiopatía Hipertrófica/genética , Cardiomiopatía Hipertrófica/patología , Cardiomiopatía Hipertrófica/fisiopatología , Niño , Preescolar , Análisis Mutacional de ADN , Progresión de la Enfermedad , Electrodiagnóstico , Exones/genética , Resultado Fatal , Femenino , Pruebas Genéticas , Corazón/fisiopatología , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Enfermedades Musculares/patología , Mutación/genética , Fenotipo , Estructura Terciaria de Proteína/genéticaRESUMEN
UNLABELLED: Mutations in LMNA gene encoding two ubiquitously expressed nuclear proteins, lamins A and C, give rise to up to 7 different pathologies affecting specific tissues. Three of these disorders affect cardiac and/or skeletal muscles with atrio-ventricular conduction disturbances, dilated cardiomyopathy and sudden cardiac death as common features. RESULTS: A new LMNA mutation (1621C>T, R541C) was found in two members of a French family with a history of ventricular rhythm disturbances and an uncommon form of systolic left ventricle dysfunction. The two patients: the proband and his daughter, were affected and exhibited an atypical form of dilated cardiomyopathy with an unexplained left ventricle aneurysm revealed by ventricular rhythm disturbances without atrio-ventricular block. CONCLUSION: This finding reinforces the highly variable phenotypic expression of LMNA mutation and emphasizes the fact that LMNA mutations can be associated with different cardiac phenotypes.
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Aneurisma Cardíaco/genética , Ventrículos Cardíacos/patología , Lamina Tipo A/genética , Adulto , Cardiomiopatía Dilatada , Análisis Mutacional de ADN , Femenino , Aneurisma Cardíaco/patología , Humanos , Masculino , Persona de Mediana Edad , Linaje , Fenotipo , Disfunción Ventricular Izquierda/etiología , Disfunción Ventricular Izquierda/genéticaRESUMEN
INTRODUCTION: Limb girdle muscular dystrophy type 1b (LGMD1B), due to LMNA gene mutations, is a relatively rare form of LGMD characterized by proximal muscle involvement associated with heart involvement comprising atrio-ventricular conduction blocks and dilated cardiomyopathy. Its clinical and genetic diagnosis is crucial for cardiac management and genetic counselling. Seven LMNA mutations have been previously reported to be responsible for LGMD1B. PATIENTS AND METHODS: We describe the neurological and cardiologic features of 14 patients belonging to 8 families in whom we identified 6 different LMNA mutations, 4 of them having never been reported. Results. Eleven patients had an LGMD1B phenotype with scapulohumeral and pelvic-femoral involvement. Thirteen patients had cardiac disease associating conduction defects (12 patients) or arrhythmias (9 patients). Seven patients needed cardiac device (pacemaker or implantable cardiac defibrillator) and two had heart transplantation. CONCLUSION: This study allowed us to specify the clinical characteristics of this entity and to outline the first phenotype/genotype relations resulting from these observations.
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Laminas/genética , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/fisiopatología , Conducción Nerviosa/fisiología , Adolescente , Adulto , Anciano , Arritmias Cardíacas/etiología , Arritmias Cardíacas/fisiopatología , Biomarcadores , Creatina Quinasa/sangre , Ecocardiografía , Electrocardiografía , Femenino , Sistema de Conducción Cardíaco/fisiopatología , Cardiopatías/diagnóstico por imagen , Cardiopatías/etiología , Cardiopatías/genética , Humanos , Lamina Tipo A , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/complicaciones , Mutación/genética , Mutación/fisiología , Linaje , Fenotipo , Tomografía Computarizada por Rayos XRESUMEN
The authors report the clinical and histologic phenotypes of a LGMD1B family including a newborn child with a homozygous LMNA nonsense mutation (Y259X). At the heterozygous state the nonsense mutation leads to a classic LGMD1B phenotype; the homozygous LMNA nonsense mutation causes a lethal phenotype.
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Codón sin Sentido , Genes Letales , Lamina Tipo A/genética , Adulto , Anciano , Consanguinidad , Resultado Fatal , Femenino , Homocigoto , Humanos , Recién Nacido , Masculino , Linaje , FenotipoRESUMEN
Laminopathies are caused by mutations in the LMNA gene encoding the ubiquitous proteins lamins A/C that are components of the lamina, a fibrous meshwork located at the inner face of the nuclear envelope. Laminopathies may affect one or several tissues such as striated muscles, peripheral nerves and adipose tissue in isolate or combined fashion. This review focuses on laminopathies affecting the striated muscle tissue only, namely Emery-Dreifuss muscular dystrophy (EDMD), limb girdle muscular dystrophy type 1B (LGMD1B) and dilated cardiomyopathy with conduction defects (DCM-CD). The phenotype of animal models in which the same mutation as that identified in EDMD or DCM-CD patients has been reproduced is presented as well as the pathophysiological mechanisms known to date.
Asunto(s)
Lamina Tipo A/genética , Laminas/fisiología , Distrofia Muscular de Emery-Dreifuss/fisiopatología , Animales , Cardiomiopatía Dilatada/diagnóstico , Modelos Animales de Enfermedad , Humanos , Leucina/genética , Músculo Esquelético/fisiopatología , Distrofia Muscular de Cinturas/diagnóstico , Distrofia Muscular de Emery-Dreifuss/diagnóstico , Miocardio , Membrana Nuclear/genética , Prolina/genéticaRESUMEN
Mutations in LMNA, the gene that encodes nuclear lamins A and C, cause up to eight different diseases collectively referred to as "laminopathies." These diseases affect striated muscle, adipose tissue, peripheral nerve, and bone, or cause features of premature aging. We investigated the consequences of LMNA mutations on nuclear architecture in skin fibroblasts from 13 patients with different laminopathies. Western-blotting showed that none of the mutations examined led to a decrease in cellular levels of lamin A or C. Regardless of the disease, we observed honeycomb nuclear structures and nuclear envelope blebs in cells examined by immunofluorescence microscopy. Concentrated foci of lamin A/C in the nucleoplasm were also observed. Only mutations in the head and tail domains of lamins A and C significantly altered the nuclear architecture of patient fibroblasts. These results confirm that mutations in lamins A and C may lead to a weakening of a structural support network in the nuclear envelope in fibroblasts and that nuclear architecture changes depend upon the location of the mutation in different domains of lamin A/C.