Implicación del cromosoma X en el retraso mental hereditarioIdentificación y caracterización de genes candidatos.

Abstract

Due to its relative high prevalence, mental retardation constitutes a social and a health problem, and it worsens in the case of hereditary conditions. Several studies have shown that X-linked mental retardation can especially be regarded as one of the major causes of mild to moderate intellectual handicap, showing a cumulative incidence of 1:300 to 1:600 males. In this work we have analysed nine different families: seven of them were affected by non-specific X-linked mental retardation, one suffered from Prieto syndrome and another from Lenz syndrome. In addition, a sporadic patient of Coffin-Lowry syndrome was analysed for mutations in the RPS6KA3 gene. In the case of the non-specific forms, we focused mainly in the Xp22 region, where 13 genes were screened for mutations. The patients of one family displayed a nucleotide change in one of these genes (FLJ14503), that could not be found neither in database sequences nor in control samples. Analysis of the protein encoded by this gene revealed that it might be a novel microtubule associated protein, but its implication in mental retardation remains yet to be proven. Two other genes were screened in Xq24-q25, but no mutations were found. In order to identify the gene responsible for the Prieto syndrome, 13 genes in the Xp11.4 region were screened by sequencing, but none of them could be implicated in the disease. A two base pair deletion in the PQBP1 gene was found to be the cause of the disease phenotype in the Lenz syndrome affected patients. This finding does not only broaden the allelic heterogeneity already described for PQBP1 mutations, it also increases the genetic heterogeneity of the Lenz syndrome itself, as PQBP1 would be the third locus associated with the disease. Analysis of the RPS6KA3 gene showed a de novo insertion of a defective LINE L1 element as the responsible mutation in the Coffin-Lowry patient. The element has inserted close to the splice donor site of intron 3, leading to the skipping of exon 4 in the processed mRNA and the disruption of the reading frame.