RESUMEN
OBJECTIVE: To characterize the pattern and extent of muscle weakness and impact on physical functioning in adults with GNEM. METHODS: Strength and function were assessed in GNEM subjects (n = 47) using hand-held dynamometry, manual muscle testing, upper and lower extremity functional capacity tests, and the GNEM-Functional Activity Scale (GNEM-FAS). RESULTS: Profound upper and lower muscle weakness was measured using hand-held dynamometry in a characteristic pattern, previously described. Functional tests and clinician-reported outcomes demonstrated the consequence of muscle weakness on physical functioning. CONCLUSIONS: The characteristic pattern of upper and lower muscle weakness associated with GNEM and the resulting functional limitations can be reliably measured using these clinical outcome assessments of muscle strength and function.
Asunto(s)
Fuerza Muscular/genética , Debilidad Muscular/etiología , Músculo Esquelético/fisiopatología , Miositis por Cuerpos de Inclusión/congénito , Adolescente , Adulto , Anciano , Femenino , Humanos , Extremidad Inferior/fisiopatología , Masculino , Persona de Mediana Edad , Actividad Motora/genética , Miositis por Cuerpos de Inclusión/complicaciones , Miositis por Cuerpos de Inclusión/genética , Ácido N-Acetilneuramínico/genética , Adulto JovenRESUMEN
Individuals with inclusion body myopathy type 3 (IBM3) display congenital joint contractures with early-onset muscle weakness that becomes more severe in adulthood. The disease arises from an autosomal dominant point mutation causing an E706K substitution in myosin heavy chain type IIa. We have previously expressed the corresponding myosin mutation (E701K) in homozygous Drosophila indirect flight muscles and recapitulated the myofibrillar degeneration and inclusion bodies observed in the human disease. We have also found that purified E701K myosin has dramatically reduced actin-sliding velocity and ATPase levels. Since IBM3 is a dominant condition, we now examine the disease state in heterozygote Drosophila in order to gain a mechanistic understanding of E701K pathogenicity. Myosin ATPase activities in heterozygotes suggest that approximately equimolar levels of myosin accumulate from each allele. In vitro actin sliding velocity rates for myosin isolated from the heterozygotes were lower than the control, but higher than for the pure mutant isoform. Although sarcomeric ultrastructure was nearly wild type in young adults, mechanical analysis of skinned indirect flight muscle fibers revealed a 59% decrease in maximum oscillatory power generation and an approximately 20% reduction in the frequency at which maximum power was produced. Rate constant analyses suggest a decrease in the rate of myosin attachment to actin, with myosin spending decreased time in the strongly bound state. These mechanical alterations result in a one-third decrease in wing beat frequency and marginal flight ability. With aging, muscle ultrastructure and function progressively declined. Aged myofibrils showed Z-line streaming, consistent with the human heterozygote phenotype. Based upon the mechanical studies, we hypothesize that the mutation decreases the probability of the power stroke occurring and/or alters the degree of movement of the myosin lever arm, resulting in decreased in vitro motility, reduced muscle power output and focal myofibrillar disorganization similar to that seen in individuals with IBM3.
Asunto(s)
Contractura/metabolismo , Contractura/patología , Drosophila melanogaster/metabolismo , Músculo Esquelético/fisiopatología , Miofibrillas/patología , Miosinas/metabolismo , Miositis por Cuerpos de Inclusión/congénito , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Citoesqueleto de Actina/metabolismo , Adenosina Trifosfatasas/metabolismo , Envejecimiento/patología , Animales , Fenómenos Biomecánicos , Modelos Animales de Enfermedad , Módulo de Elasticidad , Vuelo Animal/fisiología , Heterocigoto , Homocigoto , Cinética , Actividad Motora , Músculo Esquelético/patología , Proteínas Mutantes/metabolismo , Miofibrillas/ultraestructura , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Alas de Animales/fisiologíaRESUMEN
Adult-onset inherited myopathies with similar pathological features, including hereditary inclusion body myopathy (hIBM) and limb-girdle muscular dystrophy (LGMD), are a genetically heterogeneous group of muscle diseases. It is unclear whether these inherited myopathies initiated by mutations in distinct classes of genes are etiologically related. Here, we exploit a genetic model system to establish a mechanistic link between diseases caused by mutations in two distinct genes, hnRNPA2B1 and DNAJB6. Hrb98DE and mrj are the Drosophila melanogaster homologs of human hnRNPA2B1 and DNAJB6, respectively. We introduced disease-homologous mutations to Hrb98DE, thus capturing mutation-dependent phenotypes in a genetically tractable model system. Ectopic expression of the disease-associated mutant form of hnRNPA2B1 or Hrb98DE in fly muscle resulted in progressive, age-dependent cytoplasmic inclusion pathology, as observed in humans with hnRNPA2B1-related myopathy. Cytoplasmic inclusions consisted of hnRNPA2B1 or Hrb98DE protein in association with the stress granule marker ROX8 and additional endogenous RNA-binding proteins (RBPs), suggesting that these pathological inclusions are related to stress granules. Notably, TDP-43 was also recruited to these cytoplasmic inclusions. Remarkably, overexpression of MRJ rescued this phenotype and suppressed the formation of cytoplasmic inclusions, whereas reduction of endogenous MRJ by a classical loss of function allele enhanced it. Moreover, wild-type, but not disease-associated, mutant forms of MRJ interacted with RBPs after heat shock and prevented their accumulation in aggregates. These results indicate both genetic and physical interactions between disease-linked RBPs and DNAJB6/mrj, suggesting etiologic overlap between the pathogenesis of hIBM and LGMD initiated by mutations in hnRNPA2B1 and DNAJB6.
Asunto(s)
Contractura/congénito , Drosophila melanogaster/genética , Proteínas del Choque Térmico HSP40/genética , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/genética , Chaperonas Moleculares/genética , Distrofia Muscular de Cinturas/genética , Miositis por Cuerpos de Inclusión/congénito , Proteínas del Tejido Nervioso/genética , Oftalmoplejía/genética , Adulto , Edad de Inicio , Secuencia de Aminoácidos , Animales , Contractura/genética , Contractura/metabolismo , Contractura/patología , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/metabolismo , Regulación de la Expresión Génica , Proteínas del Choque Térmico HSP40/metabolismo , Ribonucleoproteína Heterogénea-Nuclear Grupo A-B/metabolismo , Ribonucleoproteínas Nucleares Heterogéneas/genética , Ribonucleoproteínas Nucleares Heterogéneas/metabolismo , Humanos , Chaperonas Moleculares/metabolismo , Datos de Secuencia Molecular , Músculos/metabolismo , Músculos/patología , Distrofia Muscular de Cinturas/metabolismo , Distrofia Muscular de Cinturas/patología , Mutación , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Proteínas del Tejido Nervioso/metabolismo , Oftalmoplejía/metabolismo , Oftalmoplejía/patología , Fenotipo , Unión Proteica , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Transducción de SeñalRESUMEN
The term hereditary inclusion-body myopathies (HIBMs) defines a group of rare muscle disorders with autosomal recessive or dominant inheritance and presence of muscle fibers with rimmed vacuoles and collection of cytoplasmic or nuclear 15-21 nm diameter tubulofilaments as revealed by muscle biopsy. The most common form of HIBM is due to mutations of the GNE gene that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. This results in abnormal sialylation of glycoproteins that possibly leads to muscle fiber degeneration. Mutations of the valosin containing protein are instead responsible for hereditary inclusion-body myopathy with Paget's disease of the bone and frontotemporal dementia (IBMPFD), with these three phenotypic features having a variable penetrance. IBMPFD probably represents a disorder of abnormal cellular trafficking of proteins and maturation of the autophagosome. HIBM with congenital joint contractures and external ophthalmoplegia is due to mutations of the Myosin Heavy Chain IIa gene that exerts a pathogenic effect through interference with filament assembly or functional defects in ATPase activity. This review illustrates the clinical and pathologic characteristics of HIBMs and the main clues available to date concerning the possible pathogenic mechanisms and therapeutic perspectives of these disorders. This article is part of a Special Issue entitled: Neuromuscular Diseases: Pathology and Molecular Pathogenesis.
Asunto(s)
Contractura/congénito , Demencia Frontotemporal , Fibras Musculares Esqueléticas , Distrofia Muscular de Cinturas , Miositis por Cuerpos de Inclusión/congénito , Oftalmoplejía , Osteítis Deformante , Animales , Contractura/enzimología , Contractura/genética , Contractura/patología , Demencia Frontotemporal/enzimología , Demencia Frontotemporal/genética , Demencia Frontotemporal/patología , Humanos , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/patología , Distrofia Muscular de Cinturas/enzimología , Distrofia Muscular de Cinturas/genética , Distrofia Muscular de Cinturas/patología , Mutación , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Miositis por Cuerpos de Inclusión/enzimología , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Ácido N-Acetilneuramínico/genética , Ácido N-Acetilneuramínico/metabolismo , Oftalmoplejía/enzimología , Oftalmoplejía/genética , Oftalmoplejía/patología , Osteítis Deformante/enzimología , Osteítis Deformante/genética , Osteítis Deformante/patología , Procesamiento Proteico-Postraduccional/genéticaRESUMEN
Hereditary Inclusion Body Myopathy (HIBM, IBM2, MIM:600737) is an autosomal recessive adult onset progressive muscle wasting disorder. It is associated with the degeneration of distal and proximal muscles, while often sparing the quadriceps. The bifunctional enzyme UDP-GlcNAc 2-epimerase/ManNAc kinase (GNE/MNK), encoded by the GNE gene, catalyzes the first two committed, rate-limiting steps in the biosynthesis of N-acetylneunaminic acid (sialic acid). Affected individuals have been identified with mutations in the GNE gene. In the present study, the GNE coding region of 136 symptomatic patients were sequenced. A total of 41 patients were found to have GNE mutations. Eight novel mutations were discovered among seven patients. Of the eight novel mutations, seven were missense (p.I150V, p.Y186C, p.M265T, p.V315T, p.N317D, p.G669R, and p.S699L) and one was nonsense (p.W495X), all of which span the epimerase, kinase, and allosteric domains of GNE. In one patient, one novel mutation was found in the allosteric region and kinase domain of the GNE gene. Mutations in the allosteric region lead to a different disease, sialuria; however, this particular mutation has not been described in patients with sialuria. The pathological significance of this variation with GNE function remains unknown and further studies are needed to identify its connection with HIBM. These findings further expand the clinical and genetic spectrum of HIBM.
Asunto(s)
Complejos Multienzimáticos/genética , Mutación , Miositis por Cuerpos de Inclusión/congénito , Adulto , Codón sin Sentido , Femenino , Humanos , Masculino , Mutación Missense , Miositis por Cuerpos de Inclusión/genética , Ácido N-Acetilneuramínico/metabolismo , Análisis de Secuencia de ADNRESUMEN
GNE myopathy is a recessive adult onset, slowly progressive distal and proximal myopathy, caused by mutations in the GNE gene. The most frequent mutation in GNE myopathy patients is the Middle Eastern founder mutation M712T. We have generated Gne (M712T/M712T) knockin mice. A high mortality rate in the first generation due to renal failure was recorded (as previously described). However, the following Gne (M712T/M712T) offspring generations could be classified into 3 phenotypic categories: severe, mild and without apparent phenotype. By further crossing between mice with no apparent phenotype, we were able to establish a colony of Gne (M712T/M712T) knockin mice with a high- and long-term survival rate, lacking any renal phenotype. These mice did not present any muscle phenotype (clinical or pathological) for up to 18 months. No correlation was found between the expression of any of the two mRNA Gne isoforms in muscle and the mouse genotype or phenotype. However, the expression of isoform 2 mRNA was significantly higher in the kidney of Gne (M712T/M712T) kidney affected mice compared with control. In contrast, the expression of UPR markers Bip, Chop and of the spliced form of XBP1, was upregulated in muscle of Gne (M712T/M712T) mice compared with controls, but was unchanged in the affected kidney. Thus, Gne defects can affect both muscle and kidney in mouse, but probably through different mechanisms.
Asunto(s)
Complejos Multienzimáticos/fisiología , Mutación Missense , Miositis por Cuerpos de Inclusión/congénito , Mutación Puntual , Sustitución de Aminoácidos , Animales , Cruzamientos Genéticos , ADN Complementario/genética , Modelos Animales de Enfermedad , Técnicas de Sustitución del Gen , Genotipo , Humanos , Riñón/enzimología , Riñón/patología , Ratones , Ratones Transgénicos , Complejos Multienzimáticos/deficiencia , Complejos Multienzimáticos/genética , Fuerza Muscular , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/enzimología , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Especificidad de Órganos , Fenotipo , Isoformas de Proteínas/genética , ARN Mensajero , Índice de Severidad de la Enfermedad , Organismos Libres de Patógenos Específicos , Respuesta de Proteína DesplegadaRESUMEN
GNE myopathy, previously termed hereditary inclusion body myopathy (HIBM), is an adult-onset neuromuscular disorder characterized by progressive muscle weakness. The disorder results from biallelic mutations in GNE, encoding UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, the key enzyme of sialic acid synthesis. GNE myopathy, associated with impaired glycan sialylation, has no approved therapy. Here we test potential sialylation-increasing monosaccharides for their effectiveness in prophylaxis (at the embryonic and neonatal stages) and therapy (after the onset of symptoms) by evaluating renal and muscle hyposialylation in a knock-in mouse model (Gne p.M712T) of GNE myopathy. We demonstrate that oral mannosamine (ManN), but not sialic acid (Neu5Ac), mannose (Man), galactose (Gal), or glucosamine (GlcN), administered to pregnant female mice has a similar prophylactic effect on renal hyposialylation, pathology and neonatal survival of mutant offspring, as previously shown for N-acetylmannosamine (ManNAc) therapy. ManN may be converted to ManNAc by a direct, yet unknown, pathway, or may act through another mode of action. The other sugars (Man, Gal, GlcN) may either not cross the placental barrier (Neu5Ac) and/or may not be able to directly increase sialylation. Because GNE myopathy patients will likely require treatment in adulthood after onset of symptoms, we also administered ManNAc (1 or 2g/kg/day for 12 weeks), Neu5Ac (2 g/kg/day for 12 weeks), or ManN (2 g/kg/day for 6 weeks) in drinking water to 6 month old mutant Gne p.M712T mice. All three therapies markedly improved the muscle and renal hyposialylation, as evidenced by lectin histochemistry for overall sialylation status and immunoblotting of specific sialoproteins. These preclinical data strongly support further evaluation of oral ManNAc, Neu5Ac and ManN as therapy for GNE myopathy and conceivably for certain glomerular diseases with hyposialylation.
Asunto(s)
Riñón/metabolismo , Monosacáridos/administración & dosificación , Músculos/metabolismo , Miositis por Cuerpos de Inclusión/congénito , Administración Oral , Animales , Femenino , Humanos , Riñón/patología , Riñón/ultraestructura , Ratones , Ratones Transgénicos , Complejos Multienzimáticos/genética , Músculos/patología , Miositis por Cuerpos de Inclusión/tratamiento farmacológico , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Ácido N-Acetilneuramínico/biosíntesisRESUMEN
We describe a novel autosomal dominant hereditary inclusion body myopathy (HIBM) that clinically mimics limb girdle muscular dystrophy in a Chinese family. We performed a detailed clinical assessment of 36 individuals spanning four generations. The age of onset ranged from the 30s to the 50s. Hip girdle, neck flexion and axial muscle weakness were involved at an early stage. This disease progressed slowly, and a shoulder girdle weakness appeared later in the disease course. Muscle biopsies showed necrotic, regenerating, and rimmed vacuolated fibers as well as congophilic inclusions in some of the fibers. Electron micrograph revealed cytoplasmic inclusions of 15-21 nm filaments. A genomewide scan and haplotype analyses were performed using an Illumina Linkage-12 DNA Analysis Kit (average spacing 0.58 cM), which traced the disease to a new locus on chromosome 7q22.1-31.1 with a maximum multi-point LOD score of 3.65. The critical locus for this unique disorder, which is currently referred to as hereditary inclusion body myopathy 4 (HIBM4), spans 8.78 Mb and contains 65 genes. This localization raises the possibility that one of the genes clustered within this region may be involved in this disorder.
Asunto(s)
Mapeo Cromosómico , Cromosomas Humanos Par 7 , Contractura/congénito , Miositis por Cuerpos de Inclusión/congénito , Oftalmoplejía/genética , Adulto , Edad de Inicio , Anciano , Anciano de 80 o más Años , Contractura/diagnóstico , Contractura/genética , Diagnóstico Diferencial , Femenino , Ligamiento Genético , Haplotipos , Humanos , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Músculo Esquelético/patología , Distrofia Muscular de Cinturas/diagnóstico , Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/genética , Oftalmoplejía/diagnóstico , Linaje , Muslo/patologíaRESUMEN
Hereditary myosin myopathies are characterized by variable clinical features. Inclusion body myopathy 3 (IBM-3) is an autosomal dominant disease associated with a missense mutation (E706K) in the myosin heavy chain IIa gene. Adult patients experience progressive muscle weakness. Biopsies reveal dystrophic changes, rimmed vacuoles with cytoplasmic inclusions, and focal disorganization of myofilaments. We constructed a transgene encoding E706K myosin and expressed it in Drosophila (E701K) indirect flight and jump muscles to establish a novel homozygous organism with homogeneous populations of fast IBM-3 myosin and muscle fibers. Flight and jump abilities were severely reduced in homozygotes. ATPase and actin sliding velocity of the mutant myosin were depressed >80% compared with wild-type myosin. Light scattering experiments and electron microscopy revealed that mutant myosin heads bear a dramatic propensity to collapse and aggregate. Thus E706K (E701K) myosin appears far more labile than wild-type myosin. Furthermore, mutant fly fibers exhibit ultrastructural hallmarks seen in patients, including cytoplasmic inclusions containing aberrant proteinaceous structures and disorganized muscle filaments. Our Drosophila model reveals the unambiguous consequences of the IBM-3 lesion on fast muscle myosin and fibers. The abnormalities observed in myosin function and muscle ultrastructure likely contribute to muscle weakness observed in our flies and patients.
Asunto(s)
Contractura/congénito , Drosophila melanogaster/genética , Cuerpos de Inclusión/metabolismo , Debilidad Muscular/patología , Mutación/genética , Cadenas Pesadas de Miosina/genética , Cadenas Pesadas de Miosina/metabolismo , Miositis por Cuerpos de Inclusión/congénito , Oftalmoplejía/genética , Actinas/metabolismo , Secuencia de Aminoácidos , Animales , Animales Modificados Genéticamente , ATPasa de Ca(2+) y Mg(2+)/metabolismo , Secuencia Conservada , Contractura/genética , Contractura/fisiopatología , Homocigoto , Humanos , Cuerpos de Inclusión/patología , Cinética , Locomoción , Modelos Moleculares , Datos de Secuencia Molecular , Debilidad Muscular/genética , Debilidad Muscular/fisiopatología , Proteínas Mutantes/química , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Miofibrillas/metabolismo , Miofibrillas/ultraestructura , Cadenas Pesadas de Miosina/química , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/fisiopatología , Oftalmoplejía/fisiopatología , Estabilidad Proteica , Estructura Cuaternaria de Proteína , Estructura Secundaria de Proteína , TemperaturaRESUMEN
Both Neurofibromatosis type I (NF1) and inclusion body myopathy with Paget's disease of bone and frontotemporal dementia (IBMPFD) are autosomal dominant genetic disorders. These two diseases are fully penetrant but with high heterogeneity in phenotypes, suggesting the involvement of genetic modifiers in modulating patients' phenotypes. Although NF1 is recognized as a developmental disorder and IBMPFD is associated with degeneration of multiple tissues, a recent study discovered the direct protein interaction between neurofibromin, the protein product of the NF1 gene, and VCP/p97, encoded by the causative gene of IBMPFD. Both NF1 and VCP/p97 are critical for dendritic spine formation, which provides the cellular mechanism explaining the cognitive deficits and dementia found in patients. Moreover, disruption of the interaction between neurofibromin and VCP impairs dendritic spinogenesis. Neurofibromin likely influences multiple downstream pathways to control dendritic spinogenesis. One is to activate the protein kinase A pathway to initiate dendritic spine formation; another is to regulate the synaptic distribution of VCP and control the activity of VCP in dendritic spinogenesis. Since neurofibromin and VCP/p97 also regulate cell growth and bone metabolism, the understanding of neurofibromin and VCP/p97 in neurons may be applied to study of cancer and bone. Statin treatment rescues the spine defects caused by VCP deficiency, suggesting the potential role of statin in clinical treatment for these two diseases.
Asunto(s)
Adenosina Trifosfatasas/metabolismo , Proteínas de Ciclo Celular/metabolismo , Contractura/congénito , Espinas Dendríticas/metabolismo , Morfogénesis , Miositis por Cuerpos de Inclusión/congénito , Neurofibromina 1/metabolismo , Neuronas , Oftalmoplejía/metabolismo , Adenosina Trifosfatasas/genética , Proteínas de Ciclo Celular/genética , Contractura/genética , Contractura/metabolismo , Proteínas Quinasas Dependientes de AMP Cíclico/metabolismo , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/farmacología , Redes y Vías Metabólicas , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Neurofibromatosis 1/genética , Neurofibromatosis 1/metabolismo , Neurofibromina 1/genética , Neuronas/metabolismo , Neuronas/patología , Oftalmoplejía/genética , Proteína que Contiene ValosinaRESUMEN
Hereditary inclusion body myopathy (HIBM) is a young-adult onset autosomal recessive disorder caused by a hypomorphic rate limiting enzyme of sialic acid biosynthesis. The enzyme is UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase, and is encoded by the GNE gene. HIBM causes slowly progressive muscle weakness and atrophy. Patients are typically diagnosed at 20-30 years of age, and most patients are incapacitated and wheelchair-confined by 30-50 years of age. Some sialic acid containing glycoproteins, including neural cell adhesion molecule (NCAM), are hyposialylated in HIBM muscle biopsy samples. We developed a method to allow detection of serum NCAM sialylation using Western blot, and tested serum samples from several patients and a HIBM mouse model. Preliminary results showed a clear difference in polysialylated and hyposialylated forms of NCAM extracted from serum, and showed NCAM is hyposialylated in HIBM serum samples. This initial finding may prove useful in reducing the need for serial muscle biopsies in HIBM treatment trials. Additional studies are underway to further validate this finding and to evaluate the specificity, reliability, and robustness of this potential serum biomarker for HIBM.
Asunto(s)
Miositis por Cuerpos de Inclusión/congénito , Ácido N-Acetilneuramínico/metabolismo , Moléculas de Adhesión de Célula Nerviosa/sangre , Adulto , Animales , Western Blotting , Carbohidrato Epimerasas/genética , Modelos Animales de Enfermedad , Humanos , Ratones , Persona de Mediana Edad , Mutación , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Adulto JovenRESUMEN
Inclusion body myopathy with Paget disease of the bone and frontotemporal dementia (IBMPFD) is a multisystem degenerative disorder caused by mutations in the valosin-containing protein (VCP) gene. How missense mutations in this abundant, ubiquitously expressed, multifunctional protein lead to the degeneration of disparate tissues is unclear. VCP participates in diverse cellular functions by associating with an expanding collection of substrates and cofactors that dictate its functionality. In this issue of the JCI, Wang and colleagues have further expanded the VCP interactome by identifying neurofibromin-1 (NF1) as a novel VCP interactor in the CNS. IBMPFD-associated mutations disrupt binding of VCP to NF1, resulting in reduced synaptogenesis. Thus, aberrant interactions between VCP and NF1 may explain the dementia phenotype and cognitive delay observed in patients with IBMPFD and neurofibromatosis type 1.
Asunto(s)
Adenosina Trifosfatasas/fisiología , Proteínas de Ciclo Celular/fisiología , Contractura/congénito , Dendritas/ultraestructura , Demencia Frontotemporal/genética , Miositis por Cuerpos de Inclusión/congénito , Neurofibromatosis 1/genética , Neurofibromina 1/fisiología , Oftalmoplejía/genética , Osteítis Deformante/genética , Animales , Contractura/genética , Humanos , Miositis por Cuerpos de Inclusión/genética , Proteína que Contiene ValosinaRESUMEN
Inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD) is an autosomal dominant disorder characterized by progressive myopathy that is often accompanied by bone weakening and/or frontotemporal dementia. Although it is known to be caused by mutations in the gene encoding valosin-containing protein (VCP), the underlying disease mechanism remains elusive. Like IBMPFD, neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. Neurofibromin, the protein encoded by the NF1 gene, has been shown to regulate synaptogenesis. Here, we show that neurofibromin and VCP interact and work together to control the density of dendritic spines. Certain mutations identified in IBMPFD and NF1 patients reduced the interaction between VCP and neurofibromin and impaired spinogenesis. The functions of neurofibromin and VCP in spinogenesis were shown to correlate with the learning disability and dementia phenotypes seen in patients with IBMPFD. Consistent with the previous finding that treatment with a statin rescues behavioral defects in Nf1(+/-) mice and providing further support for our hypothesis that there is crosstalk between neurofibromin and VCP, statin exposure neutralized the effect of VCP knockdown on spinogenesis in cultured hippocampal neurons. The data presented here demonstrate that there is a link between IBMPFD and NF1 and indicate a role for VCP in synapse formation.
Asunto(s)
Adenosina Trifosfatasas/fisiología , Proteínas de Ciclo Celular/fisiología , Contractura/congénito , Dendritas/ultraestructura , Demencia Frontotemporal/genética , Miositis por Cuerpos de Inclusión/congénito , Neurofibromatosis 1/genética , Neurofibromina 1/fisiología , Oftalmoplejía/genética , Osteítis Deformante/genética , Animales , Región CA1 Hipocampal/ultraestructura , Células Cultivadas/efectos de los fármacos , Células Cultivadas/ultraestructura , Colesterol/fisiología , Contractura/genética , Contractura/patología , Dendritas/metabolismo , Demencia Frontotemporal/patología , Humanos , Discapacidades para el Aprendizaje/tratamiento farmacológico , Discapacidades para el Aprendizaje/genética , Lovastatina/farmacología , Lovastatina/uso terapéutico , Ratones , Ratones Noqueados , Mutación Missense , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Neurofibromatosis 1/patología , Neurofibromatosis 1/psicología , Neurofibromina 1/deficiencia , Neurofibromina 1/genética , Oftalmoplejía/patología , Osteítis Deformante/patología , Mutación Puntual , Mapeo de Interacción de Proteínas , Estructura Terciaria de Proteína , Células Piramidales/efectos de los fármacos , Células Piramidales/ultraestructura , Ratas , Sinapsis/ultraestructura , Proteína que Contiene ValosinaRESUMEN
The hereditary inclusion-body myopathies encompass several syndromes with autosomal recessive or dominant inheritance. Despite a different clinical presentation they all have a progressive course leading to severe disability and share similar pathologic findings at the muscle biopsy. Quadriceps-sparing autosomal recessive hereditary inclusion-body myopathy (h-IBM) is the commonest form and is tied to mutations of the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) that codes for a rate-limiting enzyme in the sialic acid biosynthetic pathway. Despite the identification of the causative gene defect, it has not been clarified how mutations of the GNE gene impair muscle homeostasis. Although several lines of evidence argue in favor of an abnormal sialylation of muscle glycoproteins playing a key role in h-IBM pathogenesis, others studies have demonstrated new functions of the GNE gene, outside the sialic acid biosynthetic pathway, that may also be relevant. This review illustrates the clinical and pathologic characteristics of h-IBM and the main clues available to date concerning the possible pathogenic mechanisms of this disorder. Understanding the molecular mechanism underlying h-IBM pathology is a fundamental requisite to plan a future attempt to therapy.
Asunto(s)
Complejos Multienzimáticos/genética , Miositis por Cuerpos de Inclusión/congénito , Músculo Cuádriceps , Ácidos Siálicos/genética , Progresión de la Enfermedad , Humanos , Cuerpos de Inclusión/metabolismo , Cuerpos de Inclusión/patología , Patrón de Herencia , Mutación , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Miositis por Cuerpos de Inclusión/patología , Miositis por Cuerpos de Inclusión/fisiopatología , Músculo Cuádriceps/enzimología , Músculo Cuádriceps/patologíaRESUMEN
BACKGROUND: Many myopathies share clinical features in common, and diagnosis often requires genetic testing. We ascertained a family in which five siblings presented with distal muscle weakness of unknown etiology. METHODS: We performed high-density genomewide linkage analysis and mutation screening of candidate genes to identify the genetic defect in the family. Preserved clinical biopsy material was reviewed to confirm the diagnosis, and reverse transcriptase PCR was used to determine the molecular effect of a splice site mutation. RESULTS: The linkage scan excluded the majority of known myopathy genes, but one linkage peak included the gene GNE, in which mutations cause autosomal recessive hereditary inclusion body myopathy type 2 (HIBM2). Muscle biopsy tissue from a patient showed myopathic features, including small basophilic fibers with vacuoles. Sequence analysis of GNE revealed affected individuals were compound heterozygous for a novel mutation in the 5' splice donor site of intron 10 (c.1816+5G>A) and a previously reported missense mutation (c.2086G>A, p.V696M), confirming the diagnosis as HIBM2. The splice site mutation correlated with exclusion of exon 10 from the transcript, which is predicted to produce an in-frame deletion (p.G545_D605del) of 61 amino acids in the kinase domain of the GNE protein. The father of the proband was heterozygous for the splice site mutation and exhibited mild distal weakness late in life. CONCLUSIONS: Our study expands on the extensive allelic heterogeneity of HIBM2 and demonstrates the value of linkage analysis in resolving ambiguous clinical findings to achieve a molecular diagnosis.
Asunto(s)
Ligamiento Genético , Técnicas de Diagnóstico Molecular/métodos , Complejos Multienzimáticos/genética , Mutación/genética , Miositis por Cuerpos de Inclusión/congénito , Miositis por Cuerpos de Inclusión/genética , Sitios de Empalme de ARN/genética , Adulto , Anciano , Análisis Mutacional de ADN , Femenino , Genes Recesivos , Genómica , Heterocigoto , Humanos , Masculino , Persona de Mediana Edad , Células Musculares/patología , Distrofia Muscular de Cinturas/genética , Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/patología , Linaje , Vacuolas/metabolismoRESUMEN
Hereditary inclusion body myopathy (HIBM) is an adult onset, slowly progressive distal and proximal myopathy. Although the causing gene, GNE, encodes for a key enzyme in the biosynthesis of sialic acid, its primary function in HIBM remains unknown. The goal of this study was to unravel new clues on the biological pathways leading to HIBM by proteomic comparison. Muscle cultures and biopsies were analyzed by two dimensional gel electrophoresis (2-DE) and the same biopsy extracts by isobaric tag for relative and absolute quantitation (iTRAQ). Proteins that were differentially expressed in all HIBM specimens versus all controls in each analysis were identified by mass spectrometry. The muscle cultures 2-DE analysis yielded 41 such proteins, while the biopsies 2-DE analysis showed 26 differentially expressed proteins. Out of the 400 proteins identified in biopsies by iTRAQ, 41 showed altered expression. In spite of the different nature of specimens (muscle primary cultures versus muscle biopsies) and of the different methods applied (2D gels versus iTRAQ) the differentially expressed proteins identified in each of the three analyses where related mainly to the same pathways, ubiquitination, stress response and mitochondrial processes, but the most robust cluster (30%) was assigned to cytoskeleton and sarcomere organization. Taken together, these findings indicate a possible novel function of GNE in the muscle filamentous apparatus that could be involved in the pathogenesis of HIBM.
Asunto(s)
Proteoma/análisis , Biopsia , Análisis por Conglomerados , Electroforesis en Gel Bidimensional , Humanos , Espectrometría de Masas , Complejos Multienzimáticos/genética , Músculo Esquelético/metabolismo , Miositis por Cuerpos de Inclusión/congénito , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/metabolismo , Proteómica/métodosRESUMEN
Homozygous mutations in the UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) gene cause hereditary inclusion body myopathy type 2 (HIBM2). We describe two unrelated American patients with novel GNE mutations. While one patient followed a typical disease course for HIBM2 with an onset at age 25 and rimmed vacuole pathology on muscle biopsy, the second patient had several features atypical for HIBM2. This patient's onset was at age 55, included distal weakness, quadriceps sparing and respiratory insufficiency. His muscle biopsy showed prominent necrosis without rimmed vacuoles. This study expands the phenotype and illustrates the clinical spectrum of HIBM2 identified in a U.S. based neuromuscular clinic.
Asunto(s)
Complejos Multienzimáticos/genética , Mutación Missense/genética , Fenotipo , Anciano , Biopsia , Femenino , Humanos , Masculino , Persona de Mediana Edad , Debilidad Muscular/patología , Músculo Esquelético/patología , Miositis por Cuerpos de Inclusión/congénito , Miositis por Cuerpos de Inclusión/diagnóstico , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/patología , Insuficiencia Respiratoria/patologíaRESUMEN
Left ventricular hypertrabeculation (LVHT) also known as noncompaction has not been reported in association with hereditary inclusion body myopathy (IBM). In a 62 year old Caucasian male, with a history of muscle stiffness, myalgias, recurrent hyper-creatin-kinase(CK)-aemia, muscle cramps particularly during cold, polyarthralgias, a family history positive for muscle cramping and muscle disease, normal clinical neurologic examination, and myogenic needle EMG, muscle biopsy was indicative of hereditary IBM. Cardiologic investigations revealed arterial hypertension, left anterior hemiblock, slight myocardial thickening, and surprisingly lone LVHT. LVHT was not associated with arrhythmias, systolic dysfunction, or cardioembolic events, No neurological or cardiac therapy was necessary. During a follow-up of 18 months neither the neurological nor the cardiologic abnormalities progressed. LVHT may also occur in patients with IBM. Patients with hereditary IBM should be investigated for cardiac involvement, which may manifest not only as myocardial damage but also as impulse propagation abnormalities.
Asunto(s)
Ventrículos Cardíacos/anomalías , Ventrículos Cardíacos/diagnóstico por imagen , Miositis por Cuerpos de Inclusión/congénito , Miositis por Cuerpos de Inclusión/diagnóstico por imagen , Disfunción Ventricular Izquierda/diagnóstico por imagen , Humanos , Masculino , Persona de Mediana Edad , Miositis por Cuerpos de Inclusión/complicaciones , Ultrasonografía , Disfunción Ventricular Izquierda/complicacionesRESUMEN
Hereditary inclusion-body myopathy (HIBM) or distal myopathy with rimmed vacuoles (DMRV) is an autosomal recessive disorder characterized by preferential involvement of distal muscles in the lower extremities, especially the anterior compartment of the legs, with relative preservation of the quadriceps.This is referred to as quadriceps-sparing myopathy. Previous reports have revealed exclusive involvement in skeletal muscles. Herein we describe two siblings with typical HIBM/DMRV. The patients developed exertional dyspnea 20-26 years after disease onset. Echocardiogram revealed a cardiomyopathy in both patients. This is the first report of the association between HIBM/DMRV and cardiomyopathy.
Asunto(s)
Cardiomiopatías/genética , Cardiomiopatías/fisiopatología , Predisposición Genética a la Enfermedad/genética , Complejos Multienzimáticos/genética , Adulto , Cardiomiopatías/diagnóstico por imagen , Disnea/genética , Femenino , Humanos , Masculino , Músculo Esquelético/patología , Músculo Esquelético/fisiopatología , Miositis por Cuerpos de Inclusión/complicaciones , Miositis por Cuerpos de Inclusión/congénito , Miositis por Cuerpos de Inclusión/genética , Miositis por Cuerpos de Inclusión/fisiopatología , Hermanos , UltrasonografíaRESUMEN
PURPOSE: Israeli investigators have identified several relatively frequent disorders due to founder point mutations in Persian (Iranian) Jews, who, for nearly three centuries up to the Islamic Revolution of 1979, were completely isolated reproductively. METHODS: Using a community-based model previously employed with Tay-Sachs disease prevention, we developed a pilot program for the Persian Jewish community of greater Los Angeles. We screened for mutations responsible for four relatively frequent autosomal recessive conditions in Persian Jews in which effective interventions are available for each: Pseudocholinesterase deficiency (butyryl cholinesterase deficiency); Congenital hypoaldosteronism (corticosterone methyl oxidase II); Autoimmune polyendocrinopathy (autoimmune regulatory element); and Hereditary Inclusion Body myopathy. RESULTS: One thousand individuals volunteered. Mutations were assessed in saliva-derived DNA and were positive for 121/1000 butyryl cholinesterase deficiency; 92/1000 Hereditary Inclusion Body myopathy; 38/1000 corticosterone methyl oxidase II; and 37/1000 autoimmune regulatory element. Ten homozygous individuals (9 butyryl cholinesterase deficiency and 1 Hereditary Inclusion Body myopathy) and 10 "at-risk" couples (seven for butyryl cholinesterase deficiency and one each for the other three disorders) were identified. These frequencies are comparable with those in Israel and indicate an extraordinary level of inbreeding, as anticipated. CONCLUSIONS: A carefully planned effort can be delivered to an "increased risk" community if detailed attention is given to planning and organization. However, availability of an effective intervention for those found to be "at-risk" or possibly affected, is essential before embarking.