RESUMEN
EAST (Epilepsy, Ataxia, Sensorineural deafness, Tubulopathy) or SeSAME (Seizures, Sensorineural deafness, Ataxia, Mental retardation, and Electrolyte imbalance) syndrome is a rare autosomal recessive syndrome first described in 2009 independently by Bockenhauer and Scholl. It is caused by mutations in KCNJ10, which encodes Kir4.1, an inwardly rectifying K+ channel found in the brain, inner ear, kidney and eye. To date, 16 mutations and at least 28 patients have been reported. In this paper, we review mutations causing EAST/SeSAME syndrome, clinical manifestations in detail, and efficacy of treatment in previously reported patients. We also report a new Latvian kindred with 4 patients. In contrast to the majority of previous reports, we found a progressive course of the disorder in terms of hearing impairment and neurologic deficit. The treatment is based on antiepileptic drugs, electrolyte replacement, hearing aids and mobility devices. Future research should concentrate on recognizing the lesions in the central nervous system to evaluate new potential diagnostic criteria and on formally evaluating intellectual disability.
Asunto(s)
Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Canales de Potasio de Rectificación Interna/genética , Convulsiones/genética , Encéfalo/anomalías , Oído Interno/anomalías , Anomalías del Ojo/genética , Pérdida Auditiva Sensorineural/epidemiología , Humanos , Discapacidad Intelectual/epidemiología , Riñón/anomalías , Letonia/epidemiología , Mutación , Fenotipo , Convulsiones/epidemiologíaRESUMEN
INTRODUCTION: Caveolinopathies are a group of untreatable, degenerative muscle diseases associated with caveolin 3 (CAV3) gene mutations. OBJECTIVES: The goal of this study was to characterize the role of the CAV3 gene in patients with limb-girdle muscular dystrophy, hyperCKemia, cardiomyopathies, as well as utilization of the National Genome Database in clinical applications. MATERIALS AND METHODS: We sequenced the coding region and exon/intron boundaries of CAV3 gene in 81 neuromuscular disorder patients, a sample group from the National Genome Database, consisting of 97 individuals with cardiomyopathies, and also random selection of 100 persons. Immunohistochemical staining of muscle biopsy was performed to verify findings in one case, as the setup for the project was to use less invasive molecular biology methods. RESULTS: We identified three novel sequence variations (c.183C>G, p.S61R; c.220C>A, p.R74S; c.220C>T, p.R74C) and found evidence that one was associated with hypercreatine kinase-emia. Two previously reported mutations in families with limb-girdle muscular dystrophy were found. No mutations were identified in the cohort of patients with cardiomyopathies. DISCUSSION: CAV3 gene encodes muscle-specific protein with dominant negative type of missense mutations in it causing various phenotypes. Our study confirmed CAV3 gene involvement in neuromuscular disorders, but found no evidence in the group of patients with cardiomyopathies. Persons included in the National Genome Database could be screened for late onset Mendelian diseases.
Asunto(s)
Caveolina 3/genética , Enfermedades Neuromusculares/genética , Adulto , Cardiomiopatías/genética , Creatina Quinasa/sangre , Femenino , Humanos , Masculino , Persona de Mediana Edad , Distrofia Muscular de Cinturas/genética , MutaciónRESUMEN
BACKGROUND: Essential tremor (ET) is the most prevalent inherited movement disorder. ET has been mapped on chromosomes 2 and 3, but causative genes are not known. METHODS: We genotyped 16 microsatellite markers in a case-control cohort consisting of 104 patients and 116 controls. RESULTS: No significant difference between allele frequencies was found. The highest difference of frequencies was found in allele 171 of the marker D2S220 (OR 0.13, 95% CI 0.02-1.03, P = 0.05). In addition, we investigated the distribution of suspected disease gene DRD3 Ser9Gly polymorphism in the same patients and controls. CONCLUSION: There was not a significant difference in genotypic distribution between disease group and control subjects (chi2 =2.8, P = 0.25).
Asunto(s)
Temblor Esencial/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Estudios de Casos y Controles , Mapeo Cromosómico , Temblor Esencial/epidemiología , Femenino , Ligamiento Genético , Predisposición Genética a la Enfermedad , Humanos , Letonia/epidemiología , Masculino , Repeticiones de Microsatélite , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Receptores de Dopamina D3/genéticaRESUMEN
The transcription factor NF-ATc that controls gene expression in T lymphocytes and embryonic cardiac cells is expressed in three prominent isoforms. This is due to alternative splice/polyadenylation events that lead to the predominant synthesis of two long isoforms in naive T cells and a shorter NF-ATc isoform in effector T cells. Whereas the previously described isoform NF-ATc/A contains a relatively short C terminus, the longer isoforms, B and C, span extra C-terminal peptides of 128 and 246 aa, respectively. We show here that in addition to the strong N-terminal trans-activation domain, TAD-A, which is common to all three NF-ATc isoforms, NF-ATc/C contains a second trans-activation domain, TAD-B, in its C-terminal peptide. Various stimuli of T cells that induce the activity of TAD-A also enhance the activity of TAD-B, but, unlike TAD-A, TAD-B remains unphosphorylated by protein from 12-O-tetradecanoyl 12-phorbol 13-acetate-stimulated T cells. The shorter C-terminal peptide of isoform NF-ATc/B exerts a suppressive transcriptional effect. These properties of NF-ATc/B and -C might be of importance for gene regulation in naive T lymphocytes in which NF-ATc/B and -C are predominantly synthesized.
Asunto(s)
Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/fisiología , Proteínas Nucleares , Linfocitos T/metabolismo , Factores de Transcripción/biosíntesis , Factores de Transcripción/fisiología , Secuencia de Aminoácidos , Núcleo Celular/metabolismo , Células Cultivadas , Proteínas de Unión al ADN/química , Humanos , Activación de Linfocitos/efectos de los fármacos , Linfocinas/biosíntesis , Datos de Secuencia Molecular , Factores de Transcripción NFATC , Fragmentos de Péptidos/química , Fragmentos de Péptidos/metabolismo , Isoformas de Proteínas/biosíntesis , Isoformas de Proteínas/química , Isoformas de Proteínas/fisiología , Estructura Terciaria de Proteína , Linfocitos T/química , Linfocitos T/inmunología , Acetato de Tetradecanoilforbol/farmacología , Factores de Transcripción/química , Activación Transcripcional/inmunologíaRESUMEN
The transcription factor NF-ATc is synthesized in three prominent isoforms. These differ in the length of their C terminal peptides and mode of synthesis. Due to a switch from the use of a 3' polyA site to a more proximal polyA site, NF-ATc expression switches from the synthesis of the two longer isoforms in naive T cells to that of short isoform A in T effector cells. The relative low binding affinity of cleavage stimulation factor CstF-64 to the proximal polyA site seems to contribute to its neglect in naive T cells. These alternative polyadenylation events ensure the rapid accumulation of high concentrations of NF-ATc necessary to exceed critical threshold levels of NF-ATc for gene induction in effector T cells.