RESUMO
The mitochondrial phosphate carrier SLC25A3 transports inorganic phosphate into the mitochondrial matrix, which is essential for the aerobic synthesis of adenosine triphosphate (ATP). We identified a homozygous mutation--c.215G-->A (p.Gly72Glu)--in the alternatively spliced exon 3A of this enzyme in two siblings with lactic acidosis, hypertrophic cardiomyopathy, and muscular hypotonia who died within the 1st year of life. Functional investigation of intact mitochondria showed a deficiency of ATP synthesis in muscle but not in fibroblasts, which correlated with the tissue-specific expression of exon 3A in muscle versus exon 3B in fibroblasts. The enzyme defect was confirmed by complementation analysis in yeast. This is the first report of patients with mitochondrial phosphate-carrier deficiency.
Assuntos
Mitocôndrias Cardíacas/metabolismo , Mitocôndrias Musculares/metabolismo , Proteínas Mitocondriais/deficiência , Mutação/genética , Fosforilação Oxidativa , Proteínas de Transporte de Fosfato/deficiência , Fosfatos/metabolismo , Acidose Láctica/complicações , Acidose Láctica/metabolismo , Trifosfato de Adenosina/metabolismo , Processamento Alternativo , Sequência de Aminoácidos , Cardiomiopatia Hipertrófica/complicações , Cardiomiopatia Hipertrófica/metabolismo , Células Cultivadas , Metabolismo Energético , Éxons/genética , Feminino , Fibroblastos/metabolismo , Teste de Complementação Genética , Homozigoto , Humanos , Lactente , Recém-Nascido , Masculino , Proteínas Mitocondriais/genética , Dados de Sequência Molecular , Hipotonia Muscular/complicações , Hipotonia Muscular/metabolismo , Linhagem , Proteínas de Transporte de Fosfato/genética , Saccharomyces cerevisiae/genética , Saccharomyces cerevisiae/crescimento & desenvolvimento , Saccharomyces cerevisiae/metabolismo , Homologia de Sequência de Aminoácidos , IrmãosRESUMO
We present the clinical and laboratory features of a boy with a new syndrome of mitochondrial depletion syndrome and T cell immunodeficiency. The child suffered from severe recurrent infectious diseases, anemia, and thrombocytopenia. Clinically, he presented with severe psychomotor retardation, axial hypotonia, and a disturbed pain perception leading to debilitating biting of the thumb, lower lip, and tongue. Brain imaging showed hypoplasia of corpus callosum and an impaired myelinization of the temporo-occipital region with consecutive supratentorial hydrocephalus. Histologic examination of a skeletal muscle biopsy was normal. Biochemical investigation showed combined deficiency of respiratory chain complexes II+III and IV. MtDNA depletion was found by real-time PCR. No pathogenic mutations were identified in the TK2, SUCLA2, DGUOK, and ECGF1 genes. A heterozygous missense mutation was found in POLG1. The pathogenic relevance of this mutation is unclear. Interestingly, a lack of CD8(+) T lymphocytes as well as NK cells was also observed. The percentage of CD45RO-expressing cells was decreased in activated CD8(+) T lymphocytes. Activation of T lymphocytes via IL-2 was diminished. The occurrence of the immunologic deficiency in our patient with mtDNA depletion is a rare finding, implying that cells of the immune system might also be affected by mitochondrial disease.