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Intermediate CAG expansions in the gene ataxin-2 (ATXN2) are a known risk factor for ALS, but little is known about their role in FTD risk. Moreover, their contribution to the risk and phenotype of patients might vary in populations with different genetic backgrounds. The aim of this study was to assess the relationship of intermediate CAG expansions in ATXN2 with the risk and phenotype of ALS and FTD in the Spanish population. Repeat-primed PCR was performed in 620 ALS and 137 FTD patients in three referral centers in Spain to determine the exact number of CAG repeats. In our cohort, ≥27 CAG repeats in ATXN2 were associated with a higher risk of developing ALS (odds ratio [OR] = 2.666 [1.471-4.882]; p = 0.0013) but not FTD (odds ratio [OR] = 1.446 [0.558-3.574]; p = 0.44). Moreover, ALS patients with ≥27 CAG repeats in ATXN2 showed a shorter survival rate compared to those with <27 repeats (hazard ratio [HR] 1.74 [1.18, 2.56], p = 0.005), more frequent limb onset (odds ratio [OR] = 2.34 [1.093-4.936]; p = 0.028) and a family history of ALS (odds ratio [OR] = 2.538 [1.375-4.634]; p = 0.002). Intermediate CAG expansions of ≥27 repeats in ATXN2 are associated with ALS risk but not with FTD in the Spanish population. ALS patients carrying an intermediate expansion in ATXN2 show more frequent limb onset but a worse prognosis than those without expansions. In patients carrying C9orf72 expansions, the intermediate ATXN2 expansion might increase the penetrance and modify the phenotype.
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OBJECTIVE: To describe a new phenotype associated with a novel variant in BAG3: autosomal dominant adult-onset distal hereditary motor neuronopathy. METHODS: This study enrolled eight affected individuals from a single family and included a comprehensive evaluation of the clinical phenotype, neurophysiologic testing, muscle MRI, muscle biopsy and western blot of BAG3 protein in skeletal muscle. Genetic workup included whole exome sequencing and segregation analysis of the detected variant in BAG3. RESULTS: Seven patients developed slowly progressive and symmetric distal weakness and atrophy of lower limb muscles, along with absent Achilles reflexes. The mean age of onset was 46 years. The neurophysiological examination was consistent with the diagnosis of distal motor neuronopathy. One 57-year-old female patient was minimally symptomatic. The pattern of inheritance was autosomal dominant, with one caveat: one female patient who was an obligate carrier of the variant died at the age of 73 years without exhibiting any muscle weakness. The muscle biopsies revealed neurogenic changes. A novel heterozygous truncating variant c.1513_1514insGGAC (p.Val505GlyfsTer6) in the gene BAG3 was identified in all affected family members. CONCLUSIONS: We report an autosomal dominant adult-onset distal hereditary motor neuronopathy with incomplete penetrance in women as a new phenotype related to a truncating variant in the BAG3 gene. Our findings expand the phenotypic spectrum of BAG3-related disorders, which previously included dilated cardiomyopathy, myofibrillar myopathy and adult-onset Charcot-Marie-Tooth type 2 neuropathy. Variants in BAG3 should be considered in the differential diagnosis of distal hereditary motor neuronopathies.
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Enfermedad de Charcot-Marie-Tooth , Atrofia Muscular Espinal , Adulto , Humanos , Femenino , Persona de Mediana Edad , Anciano , Linaje , Enfermedad de Charcot-Marie-Tooth/genética , Fenotipo , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Atrofia Muscular Espinal/patología , Mutación/genética , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Reguladoras de la Apoptosis/genéticaRESUMEN
INTRODUCTION: The aim of this study is to describe the frequency and distribution of SOD1 mutations in Spain, and to explore those factors contributing to their phenotype and prognosis. METHODS: Seventeen centres shared data on amyotrophic lateral sclerosis (ALS) patients carrying pathogenic or likely pathogenic SOD1 variants. Multivariable models were used to explore prognostic modifiers. RESULTS: In 144 patients (from 88 families), 29 mutations (26 missense, 2 deletion/insertion and 1 frameshift) were found in all 5 exons of SOD1, including 7 novel mutations. 2.6% of ALS patients (including 17.7% familial and 1.3% sporadic) were estimated to carry SOD1 mutations. Its frequency varied considerably between regions, due to founder events. The most frequent mutation was p.Gly38Arg (n = 58), followed by p.Glu22Gly (n = 11), p.Asn140His (n = 10), and the novel p.Leu120Val (n = 10). Most mutations were characterized by a protracted course, and some of them by atypical phenotypes. Older age of onset was independently associated with faster disease progression (exp(Estimate) = 1.03 [0.01, 0.05], p = 0.001) and poorer survival (HR = 1.05 [1.01, 1.08], p = 0.007), regardless of the underlying mutation. Female sex was independently associated to faster disease progression (exp(Estimate) = 2.1 [1.23, 3.65], p = 0.012) in patients carrying the p.Gly38Arg mutation, resulting in shorter survival compared with male carriers (236 vs 301 months). CONCLUSIONS: These data may help to evaluate the efficacy of SOD1 targeted treatments, and to expand the number of patients that might benefit from these treatments.
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BACKGROUND: Bethlem myopathy represents the milder phenotype of collagen type VI-related myopathies. However, clinical manifestations are highly variable among patients and no phenotype-genotype correlation has been described. We aim to analyse the clinical, pathological and genetic features of a series of patients with Bethlem myopathy, and we describe seven new mutations. METHODS: A series of 16 patients with the diagnosis of Bethlem myopathy were analyzed retrospectively from their medical records for clinical, creatine kinase (CK), muscle biopsy, and muscle magnetic resonance (MRI) data. Genetic testing was performed through next-generation sequencing of custom amplicon-based targeted genes panel of myopathies. Mutations were confirmed by Sanger sequencing. RESULTS: The most frequent phenotype consisted of proximal limb weakness associated with interphalangeal and wrists contractures. However, cases with isolated contractures or isolated myopathy were found. CK levels did not correlate with severity of the disease. The most frequent mutation was the COL6A3 variant c.7447A>G, p.Lys2486Glu, with either an homozygous or compound heterozygous presentation. Five new mutations were found in COL6A1 gene and other two in COL6A3 gene, all of them with a dominant heritability pattern. From these, a new COL6A1 mutation (c.1657G>A, p.Glu553Arg) was related to an oligosymptomatic phenotype with predominating contractures in the absence of weakness and a normal muscle MRI. Finally, the most common COL6A1 mutation reported to date that leads to an Ullrich phenotype (c. 868G>A, p.Gly290Arg), has been found here as Bethlem presentation. CONCLUSIONS: Manifestations of Bethlem myopathy are quite variable, so either contractures or weakness may be lacking, and no phenotype-genotype associations can be brought.
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Contractura/genética , Distrofias Musculares/congénito , Mutación , Adulto , Anciano , Colágeno Tipo VI/genética , Contractura/diagnóstico por imagen , Contractura/patología , Creatina Quinasa/metabolismo , Femenino , Estudios de Seguimiento , Genes Dominantes , Estudios de Asociación Genética , Humanos , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Distrofias Musculares/diagnóstico por imagen , Distrofias Musculares/genética , Distrofias Musculares/patología , Fenotipo , Estudios Retrospectivos , Adulto JovenRESUMEN
Mutations in TANK binding kinase 1 (TBK1) have been linked to amyotrophic lateral sclerosis. Some TBK1 variants are nonsense and are predicted to cause disease through haploinsufficiency; however, many other mutations are missense with unknown functional effects. We exome sequenced 699 familial amyotrophic lateral sclerosis patients and identified 16 TBK1 novel or extremely rare protein-changing variants. We characterized a subset of these: p.G217R, p.R357X, and p.C471Y. Here, we show that the p.R357X and p.G217R both abolish the ability of TBK1 to phosphorylate 2 of its kinase targets, IRF3 and optineurin, and to undergo phosphorylation. They both inhibit binding to optineurin and the p.G217R, within the TBK1 kinase domain, reduces homodimerization, essential for TBK1 activation and function. Finally, we show that the proportion of TBK1 that is active (phosphorylated) is reduced in 5 lymphoblastoid cell lines derived from patients harboring heterozygous missense or in-frame deletion TBK1 mutations. We conclude that missense mutations in functional domains of TBK1 impair the binding and phosphorylation of its normal targets, implicating a common loss of function mechanism, analogous to truncation mutations.
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Esclerosis Amiotrófica Lateral/genética , Proteínas Serina-Treonina Quinasas/genética , Proteínas de Ciclo Celular , Codón sin Sentido , Exones , Femenino , Estudios de Asociación Genética , Humanos , Factor 3 Regulador del Interferón/genética , Masculino , Proteínas de Transporte de Membrana , Mutación Missense , Fosforilación , Unión Proteica , Proteínas Serina-Treonina Quinasas/química , Estructura Terciaria de Proteína , Factor de Transcripción TFIIIA/genéticaRESUMEN
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum. OBJECTIVES: The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases. METHODS: From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes. RESULTS: We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4. CONCLUSION: Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.
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Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Adulto , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/complicaciones , Proteínas de Unión al ADN/genética , Femenino , Flavoproteínas/genética , Demencia Frontotemporal/complicaciones , Humanos , Masculino , Persona de Mediana Edad , Mutación , Monoéster Fosfórico Hidrolasas/genética , Proteínas Serina-Treonina Quinasas/genética , Receptor ErbB-4/genética , Estudios Retrospectivos , Proteína Sequestosoma-1/genética , Factores Asociados con la Proteína de Unión a TATA/genética , Proteína que Contiene Valosina/genéticaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder. We screened 751 familial ALS patient whole-exome sequences and identified six mutations including p.D40G in the ANXA11 gene in 13 individuals. The p.D40G mutation was absent from 70,000 control whole-exome sequences. This mutation segregated with disease in two kindreds and was present in another two unrelated cases (P = 0.0102), and all mutation carriers shared a common founder haplotype. Annexin A11-positive protein aggregates were abundant in spinal cord motor neurons and hippocampal neuronal axons in an ALS patient carrying the p.D40G mutation. Transfected human embryonic kidney cells expressing ANXA11 with the p.D40G mutation and other N-terminal mutations showed altered binding to calcyclin, and the p.R235Q mutant protein formed insoluble aggregates. We conclude that mutations in ANXA11 are associated with ALS and implicate defective intracellular protein trafficking in disease pathogenesis.
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Esclerosis Amiotrófica Lateral/genética , Anexinas/genética , Anexinas/metabolismo , Células Madre Embrionarias Humanas/metabolismo , Humanos , Mutación/genética , Unión Proteica , Transporte de Proteínas , Proteína A6 de Unión a Calcio de la Familia S100/metabolismoAsunto(s)
Demencia Frontotemporal/genética , Enfermedad de la Neurona Motora/genética , Enfermedad de la Neurona Motora/psicología , Mutación/genética , Proteínas Serina-Treonina Quinasas/genética , Anciano , Estudios de Casos y Controles , Europa (Continente) , Femenino , Demencia Frontotemporal/complicaciones , Humanos , Masculino , Persona de Mediana Edad , LinajeRESUMEN
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Humanos , Masculino , Persona de Mediana Edad , Anciano , Apnea Obstructiva del Sueño/complicaciones , Apnea Obstructiva del Sueño/diagnóstico , Creatina Quinasa/análisis , Calambre Muscular/complicaciones , Calambre Muscular/diagnóstico , Carbamazepina/uso terapéutico , Polisomnografía/instrumentación , Polisomnografía/métodos , Debilidad Muscular/complicaciones , Anamnesis/métodos , Anamnesis/normas , Biopsia/métodos , Mialgia/complicacionesAsunto(s)
Enfermedades Musculares/genética , Miosina Tipo II/genética , Oftalmoplejía/genética , Homocigoto , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , MutaciónRESUMEN
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive degeneration of motoneurons, which is preceded by loss of neuromuscular connections in a "dying back" process. Neuregulin-1 (Nrg1) is a neurotrophic factor essential for the development and maintenance of neuromuscular junctions, and Nrg1 receptor ErbB4 loss-of-function mutations have been reported as causative for ALS. Our main goal was to investigate the role of Nrg1 type I (Nrg1-I) in SOD1(G93A) mice muscles. We overexpressed Nrg1-I by means of an adeno-associated viral (AAV) vector, and investigated its effect by means of neurophysiological techniques assessing neuromuscular function, as well as molecular approaches (RT-PCR, western blot, immunohistochemistry, ELISA) to determine the mechanisms underlying Nrg1-I action. AAV-Nrg1-I intramuscular administration promoted motor axon collateral sprouting by acting on terminal Schwann cells, preventing denervation of the injected muscles through Akt and ERK1/2 pathways. We further used a model of muscle partial denervation by transecting the L4 spinal nerve. AAV-Nrg1-I intramuscular injection enhanced muscle reinnervation by collateral sprouting, whereas administration of lapatinib (ErbB receptor inhibitor) completely blocked it. We demonstrated that Nrg1-I plays a crucial role in the collateral reinnervation process, opening a new window for developing novel ALS therapies for functional recovery rather than preservation.
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Esclerosis Amiotrófica Lateral/metabolismo , Axones/metabolismo , Neurregulina-1/metabolismo , Unión Neuromuscular/metabolismo , Quinazolinas/farmacología , Animales , Supervivencia Celular/efectos de los fármacos , Modelos Animales de Enfermedad , Lapatinib , Ratones Transgénicos , Neuronas Motoras/efectos de los fármacos , Neuronas Motoras/metabolismo , Desnervación Muscular/métodos , Neurogénesis/efectos de los fármacos , Superóxido Dismutasa-1/genética , Superóxido Dismutasa-1/metabolismoAsunto(s)
Colina Quinasa/genética , Distrofias Musculares/genética , Mutación/genética , Adulto , Complejo II de Transporte de Electrones/genética , Complejo IV de Transporte de Electrones/genética , Femenino , Humanos , Microscopía Electrónica , Músculo Esquelético/patología , Músculo Esquelético/ultraestructura , Fibras Nerviosas/patología , Fibras Nerviosas/ultraestructura , FenotipoRESUMEN
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are overlapping, fatal neurodegenerative disorders in which the molecular and pathogenic basis remains poorly understood. Ubiquitinated protein aggregates, of which TDP-43 is a major component, are a characteristic pathological feature of most ALS and FTD patients. Here we use genome-wide linkage analysis in a large ALS/FTD kindred to identify a novel disease locus on chromosome 16p13.3. Whole-exome sequencing identified a CCNF missense mutation at this locus. Interrogation of international cohorts identified additional novel CCNF variants in familial and sporadic ALS and FTD. Enrichment of rare protein-altering CCNF variants was evident in a large sporadic ALS replication cohort. CCNF encodes cyclin F, a component of an E3 ubiquitin-protein ligase complex (SCF(Cyclin F)). Expression of mutant CCNF in neuronal cells caused abnormal ubiquitination and accumulation of ubiquitinated proteins, including TDP-43 and a SCF(Cyclin F) substrate. This implicates common mechanisms, linked to protein homeostasis, underlying neuronal degeneration.
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Esclerosis Amiotrófica Lateral/genética , Ciclinas/genética , Demencia Frontotemporal/genética , Predisposición Genética a la Enfermedad/genética , Mutación Missense , Adulto , Anciano , Secuencia de Aminoácidos , Animales , Línea Celular Tumoral , Mapeo Cromosómico , Cromosomas Humanos Par 16/genética , Salud de la Familia , Femenino , Estudio de Asociación del Genoma Completo , Humanos , Masculino , Persona de Mediana Edad , Linaje , Análisis de Secuencia de ADN/métodos , Homología de Secuencia de AminoácidoAsunto(s)
Esclerosis Amiotrófica Lateral/genética , Demencia Frontotemporal/genética , Proteínas Mitocondriales/genética , Enfermedad de la Neurona Motora/genética , Edad de Inicio , Anciano , Esclerosis Amiotrófica Lateral/epidemiología , Estudios de Casos y Controles , Femenino , Demencia Frontotemporal/complicaciones , Demencia Frontotemporal/epidemiología , Humanos , Masculino , Enfermedad de la Neurona Motora/complicaciones , Enfermedad de la Neurona Motora/epidemiología , Mutación , España/epidemiologíaRESUMEN
Exome sequencing is an effective strategy for identifying human disease genes. However, this methodology is difficult in late-onset diseases where limited availability of DNA from informative family members prohibits comprehensive segregation analysis. To overcome this limitation, we performed an exome-wide rare variant burden analysis of 363 index cases with familial ALS (FALS). The results revealed an excess of patient variants within TUBA4A, the gene encoding the Tubulin, Alpha 4A protein. Analysis of a further 272 FALS cases and 5,510 internal controls confirmed the overrepresentation as statistically significant and replicable. Functional analyses revealed that TUBA4A mutants destabilize the microtubule network, diminishing its repolymerization capability. These results further emphasize the role of cytoskeletal defects in ALS and demonstrate the power of gene-based rare variant analyses in situations where causal genes cannot be identified through traditional segregation analysis.
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Esclerosis Amiotrófica Lateral/genética , Exoma/genética , Predisposición Genética a la Enfermedad , Mutación/genética , Tubulina (Proteína)/genética , Encéfalo/metabolismo , Encéfalo/patología , Humanos , Neuronas/metabolismo , Análisis de Secuencia de ADN , Tubulina (Proteína)/metabolismoRESUMEN
Hexanucleotide repeat expansions within the C9orf72 gene are the most important genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). The difficulty of developing a precise method to determine the expansion size has hampered the study of possible correlations between the hexanucleotide repeat number and clinical phenotype. Here we characterize, through a new non-radioactive Southern blot protocol, the expansion size range in a series of 38 ALS and 22 FTD heterozygous carriers of >30 copies of the repeat. Maximum, median and modal hexanucleotide repeat number were higher in ALS patients than in FTD patients (P< 0.05 in all comparisons). A higher median number of repeats correlated with a bigger range of repeat sizes (Spearman's ρ = 0.743, P = 1.05 × 10(-11)). We did not find any correlation between age of onset or disease duration with the repeat size in neither ALS nor FTD mutation carriers. Clinical presentation (bulbar or spinal) in ALS patients did not correlate either with the repeat length. We finally analyzed two families with affected and unaffected repeat expansion carriers, compared the size of the repeat expansion between two monozygotic (MZ) twins (one affected of ALS and the other unaffected), and examined the expansion size in two different tissues (cerebellum and peripheral blood) belonging to the same FTD patient. The results suggested that the length of the C9orf72 repeat varies between family members, including MZ twins, and among different tissues from the same individual.
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Esclerosis Amiotrófica Lateral/genética , Expansión de las Repeticiones de ADN , Demencia Frontotemporal/genética , Proteínas/genética , Southern Blotting/métodos , Proteína C9orf72 , Femenino , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Mutación , Gemelos MonocigóticosRESUMEN
A hexanucleotide repeat expansion in chromosome 9 open reading frame 72 (C9orf72) can cause amyotrophic lateral sclerosis (ALS) and/or frontotemporal dementia (FTD). We assessed its frequency in 781 sporadic ALS (sALS) and 155 familial ALS (fALS) cases, and in 248 Spanish controls. We tested the presence of the reported founder haplotype among mutation carriers and in 171 Ceph Europeans from Utah (CEU), 170 Yoruba Africans, 81 Han Chinese, and 85 Japanese subjects. The C9orf72 expansion was present in 27.1% of fALS and 3.2% of sALS. Mutation carriers showed lower age at onset (P = 0.04), shorter survival (P = 0.02), greater co-occurrence of FTD (P = 8.2 × 10(-5)), and more family history of ALS (P = 1.4 × 10(-20)), than noncarriers. No association between alleles within the normal range and the risk of ALS was found (P = 0.12). All 61 of the mutation carriers were tested and a patient carrying 28 hexanucleotide repeats presented with the founder haplotype. This haplotype was found in 5.6% Yoruba Africans, 8.9% CEU, 3.9% Japanese, and 1.6% Han Chinese chromosomes.
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Esclerosis Amiotrófica Lateral/genética , Expansión de las Repeticiones de ADN/genética , Predisposición Genética a la Enfermedad/genética , Proteínas/genética , África/etnología , Anciano , Anciano de 80 o más Años , Esclerosis Amiotrófica Lateral/etnología , Pueblo Asiatico/genética , Proteína C9orf72 , China/etnología , Análisis Mutacional de ADN , Etnicidad/genética , Europa (Continente)/etnología , Femenino , Frecuencia de los Genes , Predisposición Genética a la Enfermedad/etnología , Haplotipos , Heterocigoto , Humanos , Japón/etnología , Estimación de Kaplan-Meier , Masculino , Mutación , Polimorfismo de Nucleótido Simple , EspañaRESUMEN
The pathophysiological mechanisms of both familial and sporadic Amyotrophic Lateral Sclerosis (ALS) are unknown, although growing evidence suggests that skeletal muscle tissue is a primary target of ALS toxicity. Skeletal muscle biopsies were performed on transgenic SOD1(G93A) mice, a mouse model of ALS, to determine genetic biomarkers of disease longevity. Mice were anesthetized with isoflurane, and three biopsy samples were obtained per animal at the three main stages of the disease. Transcriptional expression levels of seventeen genes, Ankrd1, Calm1, Col19a1, Fbxo32, Gsr, Impa1, Mef2c, Mt2, Myf5, Myod1, Myog, Nnt, Nogo A, Pax7, Rrad, Sln and Snx10, were tested in each muscle biopsy sample. Total RNA was extracted using TRIzol Reagent according to the manufacturer's protocol, and variations in gene expression were assayed by real-time PCR for all of the samples. The Pearson correlation coefficient was used to determine the linear correlation between transcriptional expression levels throughout disease progression and longevity. Consistent with the results obtained from total skeletal muscle of transgenic SOD1(G93A) mice and 74-day-old denervated mice, five genes (Mef2c, Gsr, Col19a1, Calm1 and Snx10) could be considered potential genetic biomarkers of longevity in transgenic SOD1(G93A) mice. These results are important because they may lead to the exploration of previously unexamined tissues in the search for new disease biomarkers and even to the application of these findings in human studies.
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Esclerosis Amiotrófica Lateral/genética , Proteínas Mutantes/genética , Superóxido Dismutasa/genética , Animales , Biopsia , Desnervación , Modelos Animales de Enfermedad , Progresión de la Enfermedad , Femenino , Perfilación de la Expresión Génica , Regulación de la Expresión Génica , Marcadores Genéticos , Humanos , Longevidad/genética , Masculino , Ratones , Ratones Transgénicos , Músculo Esquelético/metabolismo , Músculo Esquelético/patología , Superóxido Dismutasa-1 , Transcripción GenéticaRESUMEN
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