Variação no número de cópias no gene MECP2 e sua relação com a deficiência intelectual em homens

Abstract

Intellectual disability (ID) is a complex condition, with a world-wide prevalence of 1-3%. Although many etiological factors associated with ID remain unclear, about 25-50% of the cases are due to genetic contributions. In this context, copy number variation (CNV) at Xq28 encompassing methyl-CpG-binding protein 2 gene (MECP2) is one of the most common cause of severe ID in males. MECP2 is highly expressed in neurons and encodes a chromatin-associated protein, which functions as a transcriptional regulator. Therefore, copy number variation in MECP2 can affect the expression of different genes in brain, leading to abnormal neurological phenotypes. In this view, in this study we conducted a CNV screening of MECP2 gene in a large cohort of 920 unrelated males with idiopathic ID. Genomic DNA was isolated from peripheral blood and MECP2 target sequences were amplified by TaqMan copy number assay®. A total of three individuals (0,33%) exhibiting duplications at MECP2 locus were detected. The duplications ranged from 420 Kb to 2 Mb and delimitation of small region of overlap demonstrated the presence of MECP2 and other seven genes (IRAK1, OPN1LM, TEX28, OPN1MW, TKTL1, FLNA and EMD). Subsequently, the segregation analysis of the duplications demonstrated that the rearrangement is de novo in the proband 565, whereas in 4219 patient the duplication was inherited from his mother, which presented an extreme skewed of X-inactivation pattern. Expression analysis in these two patients demonstrated that patient 565 has an increased expression of MECP2 gene, whereas patient 4219 has normal expression levels of this gene. Previous studies conducted in North American and European populations indicate a prevalence of 1-2% of MECP2 duplications among males with ID. Nonetheless, corroborating our results, large cohorts analysis had a lower detection rate of 0.3-0.4%. In addition, such studies indicated that duplications involving MECP2 lead to increased expression of this gene. However, considering that apparently normal expression levels of MECP2 were observed in patient 4219, our data suggests that duplications involving MECP2 gene may lead to the development of the phenotypes through other molecular mechanisms in addition to gene dosage. Alternatively, other genes involved in the rearrangements may contribute to cognitive impairments. Taken together, these data suggest that MECP2 duplications represent an important cause of idiopathic ID in males and confirms that TaqMan copy number assay® is a sensitive method to assess these duplications.