RESUMEN
Phosphoinositide-phospholipase C ß1 (PLCß1) plays a crucial role in the initiation of the genetic program responsible for muscle differentiation. We previously demonstrated that nuclear PLCß1 activates the cyclin D3 promoter during the differentiation of myoblasts to myotubes, indicating that PLCß1 is essential for cyclin D3 promoter activation and gene transcription, through c-jun/AP1. Myotonic dystrophy (DM) is the most prevalent form of muscular dystrophy in adults. DM type 1 (DM1) and type 2 (DM2) are dominantly inherited multisystem disorders. DM1 is triggered by the pathological expansion of a (CTG)(n) triplet repeat in the gene coding for DMPK, the dystrophia myotonica-protein kinase, whereas a (CCTG)(n) tetranucleotide repeat expansion in the ZNF9 gene, encoding a CCHC-type zinc finger protein, causes DM2. We found that, unlike in normal myotubes, the level of expression of PLCß1 in DM1 and DM2 cells was already elevated in proliferating cells. Treatment with insulin induced a dramatic decrease in the amount of PLCß1. During differentiation, cyclin D3 and myogenin were elevated in normal myotubes, whereas differentiating DM1 and DM2 cells did not increase these proteins. Forced expression of PLCß1 in DM1 and DM2 cells increased the expression of differentiation markers, myogenin and cyclin D3, and enhanced fusion of DM myoblasts. These results highlight again that PLCß1 expression is a key player in myoblast differentiation, functioning as a positive regulator in the correction of delayed differentiation of skeletal muscle in DM human myoblasts.
Asunto(s)
Trastornos Miotónicos/enzimología , Trastornos Miotónicos/genética , Distrofia Miotónica/enzimología , Distrofia Miotónica/genética , Fosfolipasa C beta/genética , Fosfolipasa C beta/metabolismo , Diferenciación Celular/genética , Diferenciación Celular/fisiología , Células Cultivadas , Ciclina D3/genética , Ciclina D3/metabolismo , Perfilación de la Expresión Génica , Humanos , Insulina/farmacología , Fibras Musculares Esqueléticas/enzimología , Fibras Musculares Esqueléticas/patología , Músculo Esquelético/enzimología , Músculo Esquelético/patología , Mioblastos Esqueléticos/efectos de los fármacos , Mioblastos Esqueléticos/enzimología , Mioblastos Esqueléticos/patología , Miogenina/genética , Miogenina/metabolismo , Proteínas Recombinantes/genética , Proteínas Recombinantes/metabolismo , Transfección , Regulación hacia ArribaRESUMEN
The purpose of this study was to describe the frequency of absent, unrecognized, or minimal myotonic discharges (MDs) in myotonic dystrophy type 2 (DM2). We performed a retrospective review of needle electromyography (EMG) data prior to genetic diagnosis in 49 DM2 patients at the Mayo Clinic. MDs were not reported on first or repeat EMG studies (n = 8) and not found in archived recordings of 4 patients (8%); archived EMG recordings (n = 4) confirmed the absence of MDs (n = 2), including 1 patient with normal insertional activity in all muscles, and misinterpretation of MDs as slow fibrillation potentials (n = 1) and complex repetitive discharge (CRD) activity (n = 1). Eight (16%) patients had minimal classic MDs with diffusely increased insertional activity, including waning-only MDs in all patients in this group with archived EMG recordings (n = 5). Diffuse MDs were found in 33 (67%) patients. Absent or minimal MDs do not exclude DM2. Over-reliance on diffuse MDs in patients who present with myopathy may lead to delay in genetic diagnosis of DM2.
Asunto(s)
Trastornos Miotónicos/genética , Distrofia Miotónica/fisiopatología , Adulto , Anciano , Cromosomas Humanos Par 3 , Creatina Quinasa/genética , Creatina Quinasa/metabolismo , Expansión de las Repeticiones de ADN , Electromiografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Contracción Muscular , Músculo Esquelético/fisiopatología , Trastornos Miotónicos/enzimología , Trastornos Miotónicos/fisiopatología , Distrofia Miotónica/clasificación , Distrofia Miotónica/enzimología , Distrofia Miotónica/genética , Estudios RetrospectivosRESUMEN
UNLABELLED: We describe a 6-year-old girl admitted with acute muscular weakness and pain which made her unable to walk. Her parents reported a 4-year history of similar episodes which occurred once or twice a year and always resolved spontaneously. Laboratory investigations showed elevated serum creatine kinase which peaked at day 2 of the attack with 18,600 U/l. Carnitine palmitoyltransferase-II deficiency was suspected based on the determination of serum acylcarnitines by tandem mass spectrometry which showed a characteristic elevation of long-chain C16 and C18:1 acylcarnitines. The diagnosis was confirmed by impaired in-vitro palmitate oxidation in blood and the detection of a homozygous substitution S113L in the carnitine palmitoyltransferase-II gene. CONCLUSION: Carnitine palmitoyltransferase-II deficiency should be included in the differential diagnosis of isolated muscular weakness even when manifesting in early childhood.