Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 3 de 3
Filtrar
Mais filtros










Base de dados
Intervalo de ano de publicação
1.
PLoS Genet ; 11(3): e1005050, 2015 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-25749076

RESUMO

Inverted repeats (IRs) can facilitate structural variation as crucibles of genomic rearrangement. Complex duplication-inverted triplication-duplication (DUP-TRP/INV-DUP) rearrangements that contain breakpoint junctions within IRs have been recently associated with both MECP2 duplication syndrome (MIM#300260) and Pelizaeus-Merzbacher disease (PMD, MIM#312080). We investigated 17 unrelated PMD subjects with copy number gains at the PLP1 locus including triplication and quadruplication of specific genomic intervals-16/17 were found to have a DUP-TRP/INV-DUP rearrangement product. An IR distal to PLP1 facilitates DUP-TRP/INV-DUP formation as well as an inversion structural variation found frequently amongst normal individuals. We show that a homology-or homeology-driven replicative mechanism of DNA repair can apparently mediate template switches within stretches of microhomology. Moreover, we provide evidence that quadruplication and potentially higher order amplification of a genomic interval can occur in a manner consistent with rolling circle amplification as predicted by the microhomology-mediated break induced replication (MMBIR) model.


Assuntos
Duplicação Gênica , Proteína Proteolipídica de Mielina/genética , Doença de Pelizaeus-Merzbacher/genética , Pontos de Quebra do Cromossomo , Inversão Cromossômica , Dosagem de Genes , Humanos
2.
Hum Mutat ; 34(8): 1160-71, 2013 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-23649844

RESUMO

Autosomal dominant leukodystrophy (ADLD) is an adult onset demyelinating disorder that is caused by duplications of the lamin B1 (LMNB1) gene. However, as only a few cases have been analyzed in detail, the mechanisms underlying LMNB1 duplications are unclear. We report the detailed molecular analysis of the largest collection of ADLD families studied, to date. We have identified the minimal duplicated region necessary for the disease, defined all the duplication junctions at the nucleotide level and identified the first inverted LMNB1 duplication. We have demonstrated that the duplications are not recurrent; patients with identical duplications share the same haplotype, likely inherited from a common founder and that the duplications originated from intrachromosomal events. The duplication junction sequences indicated that nonhomologous end joining or replication-based mechanisms such fork stalling and template switching or microhomology-mediated break induced repair are likely to be involved. LMNB1 expression was increased in patients' fibroblasts both at mRNA and protein levels and the three LMNB1 alleles in ADLD patients show equal expression, suggesting that regulatory regions are maintained within the rearranged segment. These results have allowed us to elucidate duplication mechanisms and provide insights into allele-specific LMNB1 expression levels.


Assuntos
Duplicação Gênica , Lamina Tipo B/genética , Doença de Pelizaeus-Merzbacher/genética , Adulto , Sequência de Bases , Pontos de Quebra do Cromossomo , Hibridização Genômica Comparativa , DNA/química , DNA/genética , Humanos , Lamina Tipo B/metabolismo , Dados de Sequência Molecular , Conformação de Ácido Nucleico , Doença de Pelizaeus-Merzbacher/metabolismo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo
3.
Am J Med Genet A ; 161A(7): 1638-46, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23696494

RESUMO

The objective of our study was to characterize the influence of multiple mutations in the MECP2 gene in a cohort of individuals with Rett syndrome. Further analysis demonstrated that nearly all resulted from de novo in cis mutations, where the disease severity was indistinguishable from single mutations. Our methods involved enrolling participants in the RTT Natural History Study (NHS). After providing informed consent through their parents or principal caretakers, additional molecular assessments were performed in the participants and their parents to assess the presence and location of more than one mutation in each. Clinical severity was assessed at each visit in those participants in the NHS. Non-contiguous MECP2 gene variations were detected in 12 participants and contiguous mutations involving a deletion and insertion in three participants. Thirteen of 15 participants had mutations that were in cis; four (of 13) had three MECP2 mutations; two (of 15) had mutations that were both in cis and in trans (i.e., on different alleles). Clinical severity did not appear different from NHS participants with a single similar mutation. Mutations in cis were identified in most participants; two individuals had mutations both in cis and in trans. The presence of multiple mutations was not associated with greater severity. Nevertheless, multiple mutations will require greater thought in the future, if genetic assignment to drug treatment protocols is considered.


Assuntos
Proteína 2 de Ligação a Metil-CpG/genética , Mutação , Síndrome de Rett/genética , Feminino , Humanos , Masculino , Pais , Síndrome de Rett/etiologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...