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Genes for Cognitive Function: Developments on the X Downloaded from genome.cshlp.org on October 1, 2008 - Published by Cold Spring Harbor Laboratory Press Genes for Cognitive Function: Developments on the X Jozef Gécz and John Mulley Genome Res. 2000 10: 157-163 Access the most recent version at doi:10.1101/gr.10.2.157 References This article cites 45 articles, 17 of which can be accessed free at: http://genome.cshlp.org/cgi/content/full/10/2/157#References Article cited in: http://genome.cshlp.org/cgi/content/full/10/2/157#otherarticles Email alerting Receive free email alerts when new articles cite this article - sign up in the box at the service top right corner of the article or click here To subscribe to Genome Research go to: http://genome.cshlp.org/subscriptions/ © 2000 Cold Spring Harbor Laboratory Press Downloaded from genome.cshlp.org on October 1, 2008 - Published by Cold Spring Harbor Laboratory Press Review Genes for Cognitive Function: Developments on the X Jozef Ge´cz1,2,4 and John Mulley1,3 1Department of Cytogenetics and Molecular Genetics, Centre for Medical Genetics, Women’s and Children’s Hospital (WCH), North Adelaide, SA 5006, Australia; 2Department of Pediatrics, 3Department of Genetics, University of Adelaide, Adelaide, Australia Developments in human genome research enabled the first steps toward a molecular understanding of cognitive function. That there are numerous genes on the X chromosome affecting intelligence at the lower end of the cognitive range is no longer in doubt. Naturally occurring mutations have so far led to the identification of seven genes accounting for a small proportion of familial nonspecific X-linked mental retardation. These new data indicate that normal expression of many more X-linked and autosomal genes contribute to cognitive function. The emerging knowledge implicating genes in intracellular signaling pathways provides the insight to identify as candidates other X-linked and autosomal genes regulating the normal development of cognitive function. Recent advances in unravelling the underlying molecular complexity have been spectacular but represent only the beginning, and new technologies will need to be introduced to complete the picture. The excess of males over females in the lower range of orders in hemizygous males, the X-chromosome has IQ distribution has long been recognized (Penrose become an obvious focus for beginning to map and 1938). Recent large-scale longitudinal studies have identify genes for syndromal and nonspecific MR. Syn- shown male excess at both ends of the distribution of dromal XLMR has been reviewed elsewhere (Lubs et al. IQ scores. Moreover, these differences in variance be- 1999) and lies outside the scope of the present discus- tween the two sexes (males show consistently higher sion. The purpose of this review is to summarize cur- variance), although generally small, are stable over rent knowledge of the molecular basis for nonspecific time (Hedges and Nowell 1995). These observations are mental retardation. consistent with the notion that at least a proportion of The first nonspecific XLMRs were mapped in 1988 cognitive function as measured by current tests is de- (Arveiler et al. 1988; Suthers et al. 1988). Whereas syn- termined by genes on the X chromosome. Although dromal XLMR is named on the basis of the most dis- the contribution of X-linked genes to increased IQ re- tinctive clinical features or eponomously after the dys- mains an area of controversy (Lehrke 1972; Turner and morphologists who described the associated distinctive Partington 1991; Morton 1992; Turner 1996; Lubs et al. clinical features, an alternative nomenclature system 1999), the fact that X-linked genes decrease IQ of males needed to be devised for nonspecific XLMR. Nonspe- is now well established, especially in families segregat- cific XLMR is defined as a nonprogressive genetically ing X-linked mental retardation (XLMR). heterogeneous condition that affects cognitive func- tion in the absence of other distinctive dysmorphic, Classification and Incidence of Mental Retardation metabolic, or neurologic features. The symbol MRX Mental retardation (MR) is defined as an IQ <70 and is was adopted for nonspecific X-linked MR, and sequen- ∼ subdivided into ranges: borderline ( 70), mild (50–69), tial MRX numbers beginning with MRX1 (Suthers et al. moderate (35–49), severe (20–34), and profound (<19). 1988) were applied to families that satisfied MRX cri- Prevalence is 2%–3% of the population (for review, see teria (Mulley et al. 1992). McLaren and Bryson 1987; Raynham et al. 1996; Crow The prevalence of all XLMRs is estimated to be and Tolmie 1998). MR can be a component of a more 1.66/1000 males (Glass 1991; Turner et al. 1996). Esti- complex syndrome (e.g., Down syndrome, fragile X mated incidence for MRX is 0.9–1.4/1000 males (Kerr syndrome, ATR-X syndrome), metabolic disorder (e.g., et al. 1991), a figure much higher than 0.22/1000 for phenylketonuria), or neuromuscular disorder (e.g., fragile X syndrome (Turner et al. 1996), the most com- Duchenne muscular dystrophy), or MR can be an ex- mon inherited familial MR. Although MRX is collec- clusive phenotype affecting only postnatal develop- tively more common than fragile X syndrome, each ment of cognitive function (nonspecific mental retar- MRX is individually rare. The most common MRX re- dation). Given the ease of expression of X-linked dis- mains FRAXE MR, associated with amplification of 4Corresponding author. CCG within FMR2. E-MAIL [email protected]; FAX 618 8204 7342. Currently, there are nearly 900 autosomal and X- 10:157–163 ©2000 by Cold Spring Harbor Laboratory Press ISSN 1054-9803/00 $5.00; www.genome.org Genome Research 157 www.genome.org Downloaded from genome.cshlp.org on October 1, 2008 - Published by Cold Spring Harbor Laboratory Press Ge´cz and Mulley linked entries with MR as an exclusive or inclusive phe- notype in the OMIM database (http://www.ncbi.nlm. nih.gov/Omim/). In ∼75% of these, MR is a component of a syndromal autosomal recessive or dominant phe- notype. There is no known autosomal form of familial nonspecific MR similar to MRX. A recent update on XLMR (Lubs et al. 1999) reviewed 178 XLMR entries of which 120 are syndromal (MRXS) and 58 are nonspe- cific (MRX). Recent new ascertainments of MRX fami- lies have increased the total to 75 at August 1999 (the Ninth International Workshop on Fragile X Syndrome and X-linked Mental Retardation, Strasbourg, France 1999). Although these families are slowly accumulat- ing, families of sufficient size for gene localization and assignment of an MRX symbol remain extremely rare, emphasising the need for international collaboration. Figure 1 A flow diagram of the current approaches and re- Numerous smaller families are also undoubtedly X- sources available for mapping and identification of MRX genes. linked, including some containing affected females. Currently two bags of resources are widely used, MRX families Affected females documented in the larger pedigrees (large, lod>2, and small lod<2) and individual patients with X could be affected as a result of skewed X-chromosome aberrations. Undoubtedly new technologies will play a major part in speeding up the whole process on different levels: linkage inactivation or partial dominance of the molecular de- analysis (automated genotyping, SNP analysis); candidate gene fect. characterization (based on finished or a draft human genome sequence) and expression analysis (ESTs, SAGE, cDNA microar- Resources and Approaches Leading to rays); and high-throughput mutation detection technology (DNA chips for known and new mutations, direct candidate gene mu- Gene Identification tation screen). Application of forward genetics techniques (search Since the publication of MRX1 (Suthers et al. 1988), a for interacting proteins, pathways) will add yet another dimen- significant resource of mapped MRX families has been sion to the scheme. With this knowledge, resources, and tech- nologies, the identification of autosomal genes involved in as- established, and additions remain ongoing. In the re- pects of cognitive function and understanding of its molecular cent past this was the point when the family study was basis will make a giant leap forward. abandoned. The gene localization determined by link- age in single families was too broad for positional clon- ing; very few of the potential candidate genes had been of the symptoms in the patients who have the chro- discovered, and there were no single obvious posi- mosomal aberrations. Moreover, these same genes be- tional candidate genes to screen for mutations from come instant candidates for familial MRX mapping by among the numerous genes that were known and ex- linkage to the same locations. This approach represents pressed in brain. Moreover, refinement to gene local- a lesson learned from the early positional cloning of ization was not possible because the individual MRX genes for other X-linked disorders such as Duchenne families could not be lumped together on the basis of muscular dystrophy. Precise determination of the their “common” phenotype. The approach has breakpoint at the level of the DNA sequence is facili- changed little in 5 years since Mandel (1994) lamented tated by the availability of detailed physical maps (Na- that gene identification “will ultimately depend on tional Center for Biotechnology Information, White- systematic screening of many probands for mutations head Institute at the Massachusetts Institute of Tech- in many candidate genes.” What has changed drasti- nology, Sanger Center, Washington University, Max cally has been the availability of vast resources arising Planck Institute Berlin), clone reagents (idem; Roswell from the Human Genome Project (Fig. 1). Park) and FISH, partial gene sequences (ESTs, Unigene An important focus of recent research has become clusters, THCs), rapidly growing genomic DNA se- the identification of genes affected by X-chromosomal quence data in the public domain (http:// rearrangements in patients with nonspecific MR. The www.ncbi.nlm.nih.gov/genome/seq/), and overall glo- chromosomal rearrangements include balanced (at the balization (World Wide Web) of human genome re- level of light microscopy) X; autosome translocations, search.
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