RESUMEN
Genes encoding the DNA helicase TWINKLE (C10orf2) or the two subunits of mtDNA polymerase γ (POLγ) (POLG1 and POLG2) have a direct effect on the mitochondrial DNA replication machinery and were reported in many mitochondrial disorders. Friedreich's ataxia (FRDA) is the common cause of ataxia often associated with the expansion of a GAA repeat in intron 1 of the frataxin gene (FXN). Mitochondrial DNA could be considered as a candidate modiï¬er factor for FRDA disease, since mitochondrial oxidative stress is thought to be involved in the pathogenesis of this disease. We screened the FXN, POLG1 and C10orf2 genes in a Tunisian patient with clinical features of Friedreich's ataxia-like. The results showed the absence of the expansion of a GAA triplet repeat in intron 1 of the FXN gene. Besides, the sequencing of all the exons and their flanking regions of the FXN, POLG1 and C10orf2 genes revealed the presence of intronic polymorphisms. In addition, screening of the mtDNA revealed the presence of several mitochondrial known variations and the absence of mitochondrial deletions in this patient. The detected m.16187C>T and the m.16189T>C change the order of the homopolymeric tract of cytosines between 16184 and 16193 in the mitochondrial D-loop and could lead to a mitochondrial dysfunction by inhibiting replication and affecting protein involved in the replication process of the mtDNA which could be responsible for the clinical features of Friedreich ataxia observed in the studied patient.
Asunto(s)
ADN Mitocondrial/genética , Enfermedades Mitocondriales/genética , Degeneraciones Espinocerebelosas/genética , Adolescente , Consanguinidad , ADN Helicasas/genética , Análisis Mutacional de ADN , ADN Polimerasa gamma , Replicación del ADN , ADN Polimerasa Dirigida por ADN/genética , Diagnóstico Diferencial , Vacuna contra Difteria, Tétanos y Tos Ferina , Ataxia de Friedreich/diagnóstico , Ataxia de Friedreich/genética , Vacunas contra Haemophilus , Humanos , Intrones , Proteínas de Unión a Hierro/genética , Masculino , Enfermedades Mitocondriales/clasificación , Enfermedades Mitocondriales/diagnóstico , Proteínas Mitocondriales/genética , Fenotipo , Vacuna Antipolio de Virus Inactivados , Polimorfismo Genético , Degeneraciones Espinocerebelosas/clasificación , Degeneraciones Espinocerebelosas/diagnóstico , Expansión de Repetición de Trinucleótido , Túnez , Vacunas Conjugadas , FrataxinaRESUMEN
BACKGROUND: Febrile seizures (FSs) relatively represent the most common form of childhood seizures. FSs are not thought of as a true epileptic disease but rather as a special syndrome characterized by its provoking factor (fever) and a typical range of 3 months to 5 years. Although specific genes affecting the majority of FS cases have not been identified yet, several genetic loci for FSs have been reported recently. The aim of this report is to search for the gene responsible for FSs in six affected Tunisian families. METHODS: A microsatellite marker analysis was performed on the known FS and generalized epilepsy with febrile seizures plus (GEFS+) loci. According to the results obtained by statistical analyses for the six studied families and in agreement with the involvement of SCN1B gene in the GEFS+ syndrome in previous studies, SCN1B on GEFS+1 locus was considered as one of the potential candidate genes and was tested for mutations by direct sequencing. RESULTS: A sequencing analysis of the SCN1B gene revealed a novel mutation (c.374G>T) that changed an arginine residue with leucine at position 125 of the protein. We consider that the variation R125L may affect the protein structure and stability by the loss of hydrogen bonding. Two identified single nucleotide polymorphisms that are located in a neighboring hypothetical polyadenylation were assumed to compose a putative disease-associated haplotype. CONCLUSION: Our results support that SCN1B is the gene responsible in one amongst the six FS Tunisian families studied and might contribute to the FS susceptibility for the five others.
