RESUMO
BACKGROUND: Autosomal recessive mutations in MPV17 (OMIM *137960) have been identified in the hepatocerebral form of mitochondrial DNA depletion syndrome (MDS). OBJECTIVE: To describe the clinical, morphologic, and genetic findings in 3 children with MPV17-related MDS from 2 unrelated families. DESIGN: Case report. SETTING: Academic research. MAIN OUTCOME MEASURES: We identified 3 novel pathogenic mutations in 3 children. RESULTS: Two children were homozygous for nonsense mutation p.W120X. A third child was compound heterozygous for missense mutation p.G24W and for a macrodeletion spanning MPV17 exon 8. All patients demonstrated lactic acidosis, hypoglycemia, hepatomegaly, and progressive liver failure. Neurologic symptoms manifested at a later stage of the disease. Death occurred within the first year of life in all 3 patients. CONCLUSIONS: These data confirm that MPV17 mutations are associated with a 2-stage syndrome. The first symptoms are metabolic and rapidly progress to hepatic failure. This stage is followed by neurologic involvement affecting the central and peripheral systems.
Assuntos
Encefalopatias Metabólicas/genética , Códon sem Sentido/genética , DNA Mitocondrial/genética , Falência Hepática/genética , Proteínas de Membrana/deficiência , Proteínas de Membrana/genética , Proteínas Mitocondriais/deficiência , Proteínas Mitocondriais/genética , Mutação de Sentido Incorreto/genética , Encefalopatias Metabólicas/metabolismo , Encefalopatias Metabólicas/patologia , Evolução Fatal , Feminino , Genes Recessivos , Genoma Mitocondrial/genética , Humanos , Lactente , Falência Hepática/metabolismo , Falência Hepática/patologia , Erros Inatos do Metabolismo/genética , Doenças Mitocondriais/genética , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , SíndromeRESUMO
Late infantile neuronal ceroid lipofuscinosis (LINCL) is caused by the deficiency of the lysosomal tripeptidyl peptidase-I encoded by CLN2. We previously detected in two LINCL patients a homozygous missense mutation, p.Asn286Ser, that affects a potential N-glycosylation site. We introduced the p.Asn286Ser mutation into the wild-type CLN2 cDNA and performed transient expression analysis to determine the effect on the catalytic activity, intracellular targeting, and glycosylation of the CLN2 protein. Expression of mutant p.Asn286Ser CLN2 in HEK293 cells revealed that the mutant was enzymatically inactive. Western blot analysis demonstrated that at steady state the amounts of expressed p.Asn286Ser CLN2 were reduced compared with wild-type expressing cells. The rate of synthesis and the sorting of the newly synthesized p.Asn286Ser CLN2 in the Golgi was not affected compared with wild-type CLN2 protein. The electrophoretic mobility of the immunoprecipitated mutant p.Asn286Ser CLN2 was increased by approximately 2 kDa compared with the wild-type CLN2 protein, whereas deglycosylation led to the generation of polypeptides of the same apparent size. The data suggest that mutant p.Asn286Ser CLN2 lacks one oligosaccharide chain resulting in enzymatic inactivation.
