RESUMO
In all known congenital imprinting disorders an association with aberrant methylation or mutations at specific loci was well established. However, several patients with transient neonatal diabetes mellitus (TNDM), Silver-Russell syndrome (SRS) and Beckwith-Wiedemann syndrome (BWS) exhibiting multilocus hypomethylation (MLH) have meanwhile been described. Whereas TNDM patients with MLH show clinical symptoms different from carriers with isolated 6q24 aberrations, MLH carriers diagnosed as BWS or SRS present only the syndrome-specific features. Interestingly, SRS and BWS patients with nearly identical MLH patterns in leukocytes have been identified. We now report on the molecular findings in DNA in three SRS patients with hypomethylation of both 11p15 imprinted control regions (ICRs) in leukocytes. One patient was a monozygotic (MZ) twin, another was a triplet. While the hypomethylation affected both oppositely imprinted 11p15 ICRs in leukocytes, in buccal swab DNA only the ICR1 hypomethylation was visible in two of our patients. In the non-affected MZ twin of one of these patients, aberrant methylation was also present in leukocytes but neither in buccal swab DNA nor in skin fibroblasts. Despite mutation screening of several factors involved in establishment and maintenance of methylation marks including ZFP57, MBD3, DNMT1 and DNMT3L the molecular clue for the ICR1/ICR2 hypomethylation in our patients remained unclear. Furthermore, the reason for the development of the specific SRS phenotype is not obvious. In conclusion, our data reflect the broad range of epimutations in SRS and illustrate that an extensive molecular and clinical characterization of patients is necessary.
Assuntos
Centrômero/genética , Metilação de DNA , Impressão Genômica , Síndrome de Silver-Russell/genética , Adolescente , Centrômero/metabolismo , Cromossomos Humanos Par 11/genética , Feminino , Regulação da Expressão Gênica , Humanos , Lactente , Masculino , Especificidade de Órgãos , FenótipoRESUMO
In chromosomes of peripheral lymphocytes of 35 patients with multiple sclerosis treated with azathioprine, antilymphocytic globulin or thoracic-duct drainage structural aberrations (breaks and gaps) were found at a significantly high rate. The aberration rates were increased in another ten untreated patients as well, but less so. Patients previously treated had a high aberration rate, too. The B- and C-chromosomes of patients treated with azathioprine were more frequently involved than those of control subjects. The terminal segment of the long arm of chromosome 1 was mostly affected in these patients, while in all groups there was an increase of aberrations in the centre of the long arm of the C-chromosome. The clinical significance of these chromosomal aberrations is not yet clear.