Methylated premutation of the FMR1 gene in three sisters: correlating CGG expansion and epigenetic inactivation.
Eur J Hum Genet
; 28(5): 567-575, 2020 05.
Article
em En
| MEDLINE
| ID: mdl-31804632
ABSTRACT
Fragile X syndrome (FXS) is a very frequent cause of inherited intellectual disability (ID) and autism. Most FXS patients have an expansion over 200 repeats of (CGG)n sequence ("full mutation" (FM)) located in the 5'UTR of the FMR1 gene, resulting in local DNA methylation (methylated "full mutation" (MFM)) and epigenetic silencing. The absence of the FMRP protein is responsible for the clinical phenotype of FXS. FM arises from a smaller maternal allele with 56-200 CGG repeats ("premutation" (PM)) during maternal meiosis. Carriers of PM alleles, which are typically unmethylated, can manifest other clinical features (primary ovarian insufficiency (POI) or FXS-associated tremor-ataxia syndrome (FXTAS)), known as fragile X-related disorders. In FXS families, rare males who have inherited an unmethylated "full mutation" (UFM) have been described. These individuals produce enough FMRP to allow normal intellectual functioning. Here we report the rare case of three sisters with a completely methylated PM of around 140 CGGs and detail their neuropsychological function. X inactivation analysis confirmed that the three sisters have a random inactivation of the X chromosome, suggesting that the PM allele is always methylated also when residing on the active X. We propose that in exceptional cases, just as the FM may be unmethylated, also a PM allele may be fully methylated. To our knowledge, females with a methylated PM allele and a mild impairment have reported only once. The study of these atypical individuals demonstrates that the size of the CGG expansion is not as tightly coupled to methylation as previously thought.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Metilação de DNA
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Expansão das Repetições de Trinucleotídeos
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Epigênese Genética
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Proteína do X Frágil da Deficiência Intelectual
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Inativação do Cromossomo X
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Síndrome do Cromossomo X Frágil
Limite:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
Eur J Hum Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
Itália