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1.
Blood ; 124(3): 437-40, 2014 Jul 17.
Artículo en Inglés | MEDLINE | ID: mdl-24735966

RESUMEN

Pearson marrow pancreas syndrome (PS) is a multisystem disorder caused by mitochondrial DNA (mtDNA) deletions. Diamond-Blackfan anemia (DBA) is a congenital hypoproliferative anemia in which mutations in ribosomal protein genes and GATA1 have been implicated. Both syndromes share several features including early onset of severe anemia, variable nonhematologic manifestations, sporadic genetic occurrence, and occasional spontaneous hematologic improvement. Because of the overlapping features and relative rarity of PS, we hypothesized that some patients in whom the leading clinical diagnosis is DBA actually have PS. Here, we evaluated patient DNA samples submitted for DBA genetic studies and found that 8 (4.6%) of 173 genetically uncharacterized patients contained large mtDNA deletions. Only 2 (25%) of the patients had been diagnosed with PS on clinical grounds subsequent to sample submission. We conclude that PS can be overlooked, and that mtDNA deletion testing should be performed in the diagnostic evaluation of patients with congenital anemia.


Asunto(s)
Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Anemia de Diamond-Blackfan/diagnóstico , Anemia de Diamond-Blackfan/genética , ADN Mitocondrial/genética , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/genética , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Acil-CoA Deshidrogenasa de Cadena Larga/genética , Niño , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea , Análisis Mutacional de ADN , Diagnóstico Diferencial , Humanos , Lactante , Mutación , Eliminación de Secuencia
2.
Stem Cells ; 31(7): 1287-97, 2013 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-23400930

RESUMEN

In congenital mitochondrial DNA (mtDNA) disorders, a mixture of normal and mutated mtDNA (termed heteroplasmy) exists at varying levels in different tissues, which determines the severity and phenotypic expression of disease. Pearson marrow pancreas syndrome (PS) is a congenital bone marrow failure disorder caused by heteroplasmic deletions in mtDNA. The cause of the hematopoietic failure in PS is unknown, and adequate cellular and animal models are lacking. Induced pluripotent stem (iPS) cells are particularly amenable for studying mtDNA disorders, as cytoplasmic genetic material is retained during direct reprogramming. Here, we derive and characterize iPS cells from a patient with PS. Taking advantage of the tendency for heteroplasmy to change with cell passage, we isolated isogenic PS-iPS cells without detectable levels of deleted mtDNA. We found that PS-iPS cells carrying a high burden of deleted mtDNA displayed differences in growth, mitochondrial function, and hematopoietic phenotype when differentiated in vitro, compared to isogenic iPS cells without deleted mtDNA. Our results demonstrate that reprogramming somatic cells from patients with mtDNA disorders can yield pluripotent stem cells with varying burdens of heteroplasmy that might be useful in the study and treatment of mitochondrial diseases.


Asunto(s)
ADN Mitocondrial/genética , Células Madre Pluripotentes Inducidas/fisiología , Enfermedades Mitocondriales/genética , Acil-CoA Deshidrogenasa de Cadena Larga/deficiencia , Acil-CoA Deshidrogenasa de Cadena Larga/metabolismo , Anemia Sideroblástica/genética , Anemia Sideroblástica/metabolismo , Anemia Sideroblástica/patología , Diferenciación Celular/genética , Línea Celular , Preescolar , Síndromes Congénitos de Insuficiencia de la Médula Ósea , ADN Mitocondrial/metabolismo , Femenino , Fibroblastos/citología , Fibroblastos/metabolismo , Fibroblastos/fisiología , Células Madre Hematopoyéticas/citología , Células Madre Hematopoyéticas/metabolismo , Células Madre Hematopoyéticas/fisiología , Humanos , Células Madre Pluripotentes Inducidas/citología , Células Madre Pluripotentes Inducidas/metabolismo , Errores Innatos del Metabolismo Lipídico/diagnóstico , Errores Innatos del Metabolismo Lipídico/metabolismo , Errores Innatos del Metabolismo Lipídico/patología , Enfermedades Mitocondriales/diagnóstico , Enfermedades Mitocondriales/metabolismo , Enfermedades Mitocondriales/patología , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/metabolismo , Enfermedades Musculares/patología , Eliminación de Secuencia
3.
Pediatr Blood Cancer ; 59(2): 311-4, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22532422

RESUMEN

Dyskeratosis congenita (DC) is a rare inherited bone marrow failure syndrome caused by mutations in seven genes involved in telomere biology, with approximately 50% of cases remaining genetically uncharacterized. We report a patient with classic DC carrying a compound heterozygous mutation in the CTC1 (conserved telomere maintenance component 1) gene, which has recently implicated in the pleiotropic syndrome Coats plus. This report confirms a molecular link between DC and Coats plus and expands the genotype-phenotype complexity observed in telomere-related genetic disorders.


Asunto(s)
Disqueratosis Congénita/genética , Mutación/genética , Telangiectasia Retiniana/genética , Proteínas de Unión a Telómeros/genética , Adolescente , Femenino , Citometría de Flujo , Heterocigoto , Humanos , Hibridación Fluorescente in Situ , Telómero/genética , Tomografía Computarizada por Rayos X
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