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1.
Hum Mol Genet ; 24(13): 3708-17, 2015 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-25839420

RESUMEN

DNA double-strand breaks (DSBs) are highly toxic lesions, which, if not properly repaired, can give rise to genomic instability. Non-homologous end-joining (NHEJ), a well-orchestrated, multistep process involving numerous proteins essential for cell viability, represents one major pathway to repair DSBs in mammalian cells, and mutations in different NHEJ components have been described in microcephalic syndromes associated, e.g. with short stature, facial dysmorphism and immune dysfunction. By using whole-exome sequencing, we now identified in three affected brothers of a consanguineous Turkish family a homozygous mutation, c.482G>A, in the XRCC4 gene encoding a crucial component of the NHEJ pathway. Moreover, we found one additional patient of Swiss origin carrying the compound heterozygous mutations c.25delG (p.His9Thrfs*8) and c.823C>T (p.Arg275*) in XRCC4. The clinical phenotype presented in these patients was characterized by severe microcephaly, facial dysmorphism and short stature, but they did not show a recognizable immunological phenotype. We showed that the XRCC4 c.482G>A mutation, which affects the last nucleotide of exon 4, induces defective splicing of XRCC4 pre-mRNA mainly resulting in premature protein truncation and most likely loss of XRCC4 function. Moreover, we observed on cellular level that XRCC4 deficiency leads to hypersensitivity to DSB-inducing agents and defective DSB repair, which results in increased cell death after exposure to genotoxic agents. Taken together, our data provide evidence that autosomal recessive mutations in XRCC4 induce increased genomic instability and cause a NHEJ-related syndrome defined by facial dysmorphism, primary microcephaly and short stature.


Asunto(s)
Estatura , Proteínas de Unión al ADN/genética , Inestabilidad Genómica , Microcefalia/genética , Mutación Puntual , Adolescente , Niño , Femenino , Humanos , Lactante , Masculino , Microcefalia/fisiopatología , Fenotipo , Turquía
2.
Nat Genet ; 49(2): 249-255, 2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28067911

RESUMEN

Bosma arhinia microphthalmia syndrome (BAMS) is an extremely rare and striking condition characterized by complete absence of the nose with or without ocular defects. We report here that missense mutations in the epigenetic regulator SMCHD1 mapping to the extended ATPase domain of the encoded protein cause BAMS in all 14 cases studied. All mutations were de novo where parental DNA was available. Biochemical tests and in vivo assays in Xenopus laevis embryos suggest that these mutations may behave as gain-of-function alleles. This finding is in contrast to the loss-of-function mutations in SMCHD1 that have been associated with facioscapulohumeral muscular dystrophy (FSHD) type 2. Our results establish SMCHD1 as a key player in nasal development and provide biochemical insight into its enzymatic function that may be exploited for development of therapeutics for FSHD.


Asunto(s)
Atresia de las Coanas/genética , Proteínas Cromosómicas no Histona/genética , Microftalmía/genética , Mutación Missense/genética , Nariz/anomalías , Animales , Línea Celular , Preescolar , Epigénesis Genética/genética , Femenino , Predisposición Genética a la Enfermedad/genética , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Distrofia Muscular Facioescapulohumeral/genética , Xenopus laevis/genética
3.
Curr Biol ; 26(15): 2037-2043, 2016 08 08.
Artículo en Inglés | MEDLINE | ID: mdl-27426517

RESUMEN

Mitochondrial dysfunction is pervasive in human pathologies such as neurodegeneration, diabetes, cancer, and pathogen infections as well as during normal aging. Cells sense and respond to mitochondrial dysfunction by activating a protective transcriptional program known as the mitochondrial unfolded protein response (UPR(mt)), which includes genes that promote mitochondrial protein homeostasis and the recovery of defective organelles [1, 2]. Work in Caenorhabditis elegans has shown that the UPR(mt) is regulated by the transcription factor ATFS-1, which is regulated by organelle partitioning. Normally, ATFS-1 accumulates within mitochondria, but during respiratory chain dysfunction, high levels of reactive oxygen species (ROS), or mitochondrial protein folding stress, a percentage of ATFS-1 accumulates in the cytosol and traffics to the nucleus where it activates the UPR(mt) [2]. While similar transcriptional responses have been described in mammals [3, 4], how the UPR(mt) is regulated remains unclear. Here, we describe a mammalian transcription factor, ATF5, which is regulated similarly to ATFS-1 and induces a similar transcriptional response. ATF5 expression can rescue UPR(mt) signaling in atfs-1-deficient worms requiring the same UPR(mt) promoter element identified in C. elegans. Furthermore, mammalian cells require ATF5 to maintain mitochondrial activity during mitochondrial stress and promote organelle recovery. Combined, these data suggest that regulation of the UPR(mt) is conserved from worms to mammals.


Asunto(s)
Factores de Transcripción Activadores/genética , Caenorhabditis elegans/genética , Proteínas Mitocondriales/genética , Factores de Transcripción Activadores/metabolismo , Animales , Animales Modificados Genéticamente/genética , Animales Modificados Genéticamente/metabolismo , Caenorhabditis elegans/metabolismo , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Células HEK293 , Células HeLa , Humanos , Proteínas Mitocondriales/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Respuesta de Proteína Desplegada
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