X-linked mental retardation: many genes for a complex disorder
Introduction
With a prevalence of about 2%, mental retardation is the most common reason for referral to genetic services and one of the important unsolved problems in health care. Mild forms of mental retardation (i.e. intelligence quotient [IQ] of 50 to 70) are thought to represent the lower end of the normal IQ distribution and to result from the interaction of many genes and non-genetic factors. In contrast, severe forms (i.e. IQ <50, incidence ∼0.4%) might be caused by catastrophic events such as perinatal hypoxia or, more often, specific genetic factors such as chromosomal aberrations and defects of specific genes.
Mental retardation is significantly more frequent in males than in females [1, 2, 3]. This observation and the description of numerous large families with X-linked inheritance patterns [4, 5, 6] laid the foundations for the concept, now amply confirmed, that X-linked gene defects have important roles in the aetiology of mental retardation [7, 8].
Clinical and genetic observations have shown that X-linked mental retardation (XLMR) is very heterogeneous. The most common form is the fragile X mental retardation syndrome, characterized by a conspicuous cytogenetic abnormality, or fragile site, near the tip of Xq [9], which is caused by an expanded CCG triplet repeat sequence in the 5′ untranslated region (UTR) of the FMR1 (FRAGILE X MENTAL RETARDATION 1) gene, as shown by Verkerk et al. [10] and other groups. Ever since, fragile X syndrome has had a central role in XLMR research, and these studies have significantly broadened our insight into the molecular mechanisms underlying brain function in health and disease (reviewed by ST Warren, this issue). For a long time, however, other forms of XLMR received relatively little attention, apart from a mild form of XLMR, which was found to be caused by CCG repeat expansion in the 5′ UTR of another gene, FMR2 [11].
The cloning of the OLIGOPHRENIN (OPHN1) gene in 1998 [12] marked the beginning of systematic attempts to unravel the molecular causes of XLMR. Large cohorts of XLMR families were the key to the success of these efforts, which, to date, have led to the identification of more than 60 XLMR genes. Mutations in most of these give rise to clinically distinguishable syndromic forms of mental retardation, such as fragile X syndrome, Coffin-Lowry syndrome [13] or Rett syndrome [14] (see also review by HY Zoghbi, this issue). Many of these genes have also been implicated in non-syndromic XLMR (NS-XLMR). NS-XLMR is characterized by ‘pure’ cognitive impairment without other recognizable clinical signs and is thought to be more common than syndromic forms of XLMR. Recent progress in this field is reflected by the fact that in 2005 alone, six different reviews have dealt with this subject [15] or specific aspects of XLMR [16, 17, 18, 19, 20].
During the past 12 months, additional genes have been implicated in XLMR, and several syndromic forms were found to be caused by mutations in previously identified XLMR genes. Systematic screening of families with NS-XLMR is beginning to shed light on the prevalence of mutations in these genes, and, before long, efficient new diagnostic methods will become available for their detection. Arguably the most exciting observation of the past year was the demonstration that in a Drosophila model of fragile X syndrome, essential aspects of brain function were restored by the administration of drugs [21••]. This finding raises hopes that, eventually, at least some of the many forms of XLMR might be amenable to treatment.
This review provides up-to-date information on all the genes that have been implicated in syndromic and/or non-syndromic XLMR. We re-examine the possible reasons for the vast excess of males with mental retardation, which cannot be explained by X-linked recessive defects alone, including the possible existence of X-linked modifier genes that predispose to but do not cause mental retardation.
Section snippets
Novel genes implicated in non-syndromic and syndromic XLMR
The list of genes that have been implicated in non-syndromic and syndromic forms of XLMR continues to grow; at present, it comprises 61 entries (Figure 1; see also Table 1 and Supplementary Table 1). Recent additions include GRIA3, a plausible functional candidate because it encodes the AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptor GLUR3, which mediates fast synaptic transmission in the central nervous system. In three unrelated mentally retarded males, Wang and coworkers
Number and mutation frequency of XLMR genes
Approximately 4% of the more than 22 000 protein-coding genes presently listed in ENSEMBL are located on the X-chromosome, and roughly 40% of these are currently known to be expressed in the brain. Therefore, several hundred genes could be involved in XLMR, and the 61 X-chromosomal genes that have been implicated in XLMR to date (Figure 1) might be just the tip of the iceberg. In patients with NS-XLMR, which appears to be twice as common as syndromic XLMR [42], mutations have been described in
What causes the male excess in XLMR?
Recent studies suggest that the cumulative frequency of XLMR does not exceed 10%. This is much lower than should be expected by the well-documented excess of mentally retarded males; men are ∼1.4-fold more likely to have severe mental retardation, and perhaps as much as 1.9-fold more likely to have mild mental retardation (see Leonard and Wen [53]). Therefore, this excess cannot be caused by X-linked gene defects alone (for details, see Ropers and Hamel [15]. A higher prevalence in males has
Clustering of cognition genes on the X-chromosome?
In their recent compilation of Mendelian disorders that are consistently or occasionally associated with mental retardation, Inlow and Restifo [56•] concluded that the contribution of X-linked genes is significantly higher than would be expected, and that this excess cannot be explained by ascertainment biases favoring the identification of X-linked forms of mental retardation. Instead, as previously proposed [57, 58, 59], genes that are important for brain development and function might be
Prospects for diagnosis — and therapy?
Since 1998, the number of genes implicated in NS-XLMR has increased exponentially owing to the generation of large cohorts of families, which has enabled systematic mutation-screening of positional and functional candidate genes. Ongoing efforts to sequence the vast majority of the >900 X-chromosomal genes in up to 300 XLMR families [37] (L Raymond, personal communication) are a logical extension of this strategy. Undoubtedly, these and even more ambitious plans, aiming at the sequencing of all
Oulooks
In view of these developments, it is very likely that, in the foreseeable future, research into fragile X syndrome and other forms of XLMR will stay in the limelight. The identification of novel genes for X-linked mental retardation and the elucidation of their role will continue to provide new insights into the function of the human brain and will have far-reaching implications for health care.
By contrast, it is now widely accepted that XLMR is significantly less frequent than previously
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
••of outstanding interest
Acknowledgements
I thank Arjan de Brouwer (Nijmegen), Jozef Gecz, Hans van Bokhoven and other members of the European XLMR Consortium for sharing with me relevant information for this review; Ben Hamel, Andreas Kuss, Vera Kalscheuer, Andreas Tzschach and Lars Jensen for critically reading the manuscript; and Hannelore Markert for assisting me with its preparation. Our own work is supported by the Innovation Funds of the Max Planck Society and the Deutsche Forschungsgemeinschaft, Sonderforschungsbereich 577.
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