RESUMEN
Deoxyguanosine kinase (dGK) deficiency is a frequent cause of mitochondrial DNA depletion associated with a hepatocerebral phenotype. In this study, we describe a new splice site mutation in the DGUOK gene and the clinical, radiologic, and genetic features of these DGUOK patients. This new DGUOK homozygous mutation (c.444-62C>A) was identified in three patients from two North-African consanguineous families with combined respiratory chain deficiencies and mitochondrial DNA depletion in the liver. Brain MRIs are normal in DGUOK patients in the literature. Interestingly, we found subtentorial abnormal myelination and moderate hyperintensity in the bilateral pallidi in our patients. This new mutation creates a cryptic splice site in intron 3 (in position -62) and is predicted to result in a larger protein with an in-frame insertion of 20 amino acids. In silico analysis of the putative impact of the insertion shows serious clashes in protein conformation: this insertion disrupts the alpha5 helix of the dGK kinase domain, rendering the protein unable to bind purine deoxyribonucleosides. In addition, a common haplotype that segregated with the disease in both families was detected by haplotype reconstruction with 10 markers (microsatellites and SNPs), which span 4.6 Mb of DNA covering the DGUOK locus. In conclusion, we report a new DGUOK splice site mutation that provide insight into a critical protein domain (dGK kinase domain) and the first founder mutation in a North-African population.
Asunto(s)
ADN Mitocondrial/genética , Efecto Fundador , Predisposición Genética a la Enfermedad , Encefalopatía Hepática/enzimología , Encefalopatía Hepática/genética , Mutación/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Análisis Mutacional de ADN , Resultado Fatal , Regulación Enzimológica de la Expresión Génica , Genotipo , Humanos , Lactante , Imagen por Resonancia Magnética , Masculino , Linaje , Fosfotransferasas (Aceptor de Grupo Alcohol)/química , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Estructura Secundaria de Proteína , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , SíndromeRESUMEN
Cerebellar ataxia is known to occasionally occur in the course of mitochondrial disorders. We report on MR spectroscopy (1H MRS) evidence of elevated brain lactate in the cerebellar area of 11 patients with cerebellar ataxia ascribed to mitochondrial respiratory chain deficiency (RCD). 1H MRS spectroscopy evidence of lactate peak was found in the cerebellum of 9/11 cases, while no lactate was detected in the putamen in 8/11. We suggest using 1H MRS in cerebellar atrophy in the diagnosis of mitochondrial RCD.