A new gene involved in mental retardation?

Abstract

X-linked nonspecific mental retardation (MRX) affects 0.15% of males and can arise from mutations in any one of several genes on the human X chromosome. MRX patients have learning difficulties but exhibit no other consistent abnormalities. Positional cloning studies have led to the identification of seven genes involved in MRX, the majority of which are involved in intracellular signalling. However, it was known that there was another unidentified locus mapping to a,1.5 Mb interval on Xp22.3.Now, Fukami and colleagues1xA member of a gene family on Xp22.3, VCX-A, is deleted in patients with X-linked nonspecific mental retardation. Fukami, M. et al. Am. J. Hum. Genet. 2000; 67: 563–573Abstract | Full Text | Full Text PDF | PubMed | Scopus (83)See all References1 have identified VCX-A (variably charged, X chromosome mRNA on CRI-S232A) as being a strong candidate for the Xp22.3 MRX gene. The DNA of 15 males with deletions within Xp and clinical features of Xp22.3 contiguous gene-deletion syndrome were analysed. Only four of these individuals were assessed as having mental retardation. A mapping of deletion breakpoints allowed the identification of a 15-kb region absent in the four MRX patients but present in all the other patients. Only one gene, VCX-A, was found by exon trapping and sequence analysis of this region; therefore, it is likely that the absence of VCX-A is responsible for the MRX phenotype. VCX-A is a member of a family of genes with four nearly identical paralogues on Xp22.3 and two on Yq11.2. These genes are nearly identical at the sequence level, with the major difference being the number of copies of a 30-bp tandem repeat within the coding sequence. The number of repeats within VCX-A itself is polymorphic, with ten copies being the most common. The function of these genes is unknown, as they contain no recognizable motifs, although VCY was described in the databases as encoding a ‘putative DNA- or RNA-binding protein’.Several doubts remain over the involvement of VCX-A in MRX; despite the high level of sequence homology, there is no correlation between the presence or absence of the other three VCX genes and mental retardation in the patients studied. No mutations were found in any VCX genes in five MRX patients with linkage to large regions of Xp22. Furthermore, RT-PCR and northern analysis only detected expression of the VCX/VCY family of genes in adult testis. There are several possible reasons why VCX-A might not be involved in MRX; the work reported here cannot exclude the possibility of there being additional regions of Xp22.3 that are absent or mutated only in the MRX patients. Alternatively, this 15-kb region might contain parts of another gene or regulatory elements not identified by sequence analysis or exon-trapping.Whether this work will be informative for our understanding of mental retardation and, conversely, cognition hangs on whether its absence really does cause MRX. Regardless of this, the VCX/VCY gene family warrants further study for evolutionary reasons as, while being present in primates and in old and new world monkeys, it is absent in prosimians, marsupials and other mammals.