X-linked mental retardation: many genes for a complex disorder

https://doi.org/10.1016/j.gde.2006.04.017Get rights and content

X-linked mental retardation (XLMR) is a common cause of moderate to severe intellectual disability in males. XLMR is very heterogeneous, and about two-thirds of patients have clinically indistinguishable non-syndromic (NS-XLMR) forms, which has greatly hampered their molecular elucidation. A few years ago, international consortia overcame this impasse by collecting DNA and cell lines from large cohorts of XLMR families, thereby paving the way for the systematic study of the molecular causes of XLMR. Mutations in known genes might already account for 50% of the families with NS-XLMR, and various genes have been pinpointed that seem to be of particular diagnostic importance. Eventually, even therapy of XLMR might become possible, as suggested by the unexpected plasticity of the neuronal wiring in the brain, and the recent successful drug treatment of a fly model for fragile X syndrome.

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.

References (90)

  • U. Zechner et al.

    Divergent genetic and epigenetic post-zygotic isolation mechanisms in Mus and Peromyscus

    J Evol Biol

    (2004)
  • D.K. Nguyen et al.

    Dosage compensation of the active X chromosome in mammals

    Nat Genet

    (2006)
  • D.H. Skuse et al.

    Evidence from Turner's syndrome of an imprinted X-linked locus affecting cognitive function

    Nature

    (1997)
  • R. Yuste et al.

    Genesis of dendritic spines: insights from ultrastructural and imaging studies

    Nat Rev Neurosci

    (2004)
  • T. Bienvenu et al.

    ARX, a novel Prd-class-homeobox gene highly expressed in the telencephalon, is mutated in X-linked mental retardation

    Hum Mol Genet

    (2002)
  • I. Meloni et al.

    FACL4, encoding fatty acid-CoA ligase 4, is mutated in nonspecific X-linked mental retardation

    Nat Genet

    (2002)
  • F. Laumonnier et al.

    X-linked mental retardation and autism are associated with a mutation in the NLGN4 gene, a member of the neuroligin family

    Am J Hum Genet

    (2004)
  • A.M. Lossi et al.

    Abnormal expression of the KLF8 (ZNF741) gene in a female patient with an X;autosome translocation t(X;21)(p11.2;q22.3) and non-syndromic mental retardation

    J Med Genet

    (2002)
  • L.S. Penrose

    A clinical and genetic study of 1280 cases of mental defect

    (1938)
  • S.W. Wright et al.

    Investigation of families with two or more mentally defective siblings: clinical observations

    Am J Dis Child

    (1959)
  • J.H. Priest et al.

    An approach to genetic factors in mental retardation. Studies of families containing at least two siblings admitted to a state institution for the retarded

    Am J Ment Defic

    (1961)
  • J.P. Martin et al.

    A pedigree of mental defect showing sex-linkage

    J Neurol Neurosurg Psychiatry

    (1943)
  • W. Allan et al.

    Some examples of the inheritance of mental deficiency: apparently sex-linked idiocy and microcephaly

    Am J Ment Defic

    (1944)
  • H. Renpenning et al.

    Familial sex-linked mental retardation

    Can Med Assoc J

    (1962)
  • R. Lehrke

    A theory of X-linkage of major intellectual traits

    Am J Ment Defic

    (1972)
  • R.G. Lehrke

    X-linked mental retardation and verbal disability

    Birth Defects Orig Artic Ser

    (1974)
  • H.A. Lubs

    A marker X chromosome

    Am J Hum Genet

    (1969)
  • J. Gecz et al.

    Identification of the gene FMR2, associated with FRAXE mental retardation

    Nat Genet

    (1996)
  • P. Billuart et al.

    Oligophrenin-1 encodes a rhoGAP protein involved in X-linked mental retardation

    Nature

    (1998)
  • E. Trivier et al.

    Mutations in the kinase Rsk-2 associated with coffin-lowry syndrome

    Nature

    (1996)
  • R.E. Amir et al.

    Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2

    Nat Genet

    (1999)
  • H.H. Ropers et al.

    X-linked mental retardation

    Nat Rev Genet

    (2005)
  • T. Kleefstra et al.

    X-linked mental retardation: further lumping, splitting and emerging phenotypes

    Clin Genet

    (2005)
  • F.L. Raymond

    X-linked mental retardation: a clinical guide

    J Med Genet

    (2006)
  • A. Renieri et al.

    Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view

    J Cell Physiol

    (2005)
  • R.E. Stevenson

    Advances in X-linked mental retardation

    Curr Opin Pediatr

    (2005)
  • P. Billuart et al.

    Retards mentaux liés à l’X

    Med Sci (Paris)

    (2005)
  • Y. Wu et al.

    Mutations in ionotropic ampa receptor 3 (GLUR3) in males with X-linked mental retardation [abstract].

  • J. Gecz et al.

    Characterization of the human glutamate receptor subunit 3 gene (GRIA3), a candidate for bipolar disorder and nonspecific X-linked mental retardation

    Genomics

    (1999)
  • K. Kutsche et al.

    Mutations in ARHGEF6, encoding a guanine nucleotide exchange factor for Rho GTPases, in patients with X-linked mental retardation

    Nat Genet

    (2000)
  • D. Lugtenberg et al.

    ZNF674: A new Krüppel-associated box-containing zinc-finger gene involved in nonsyndromic X-linked mental retardation

    Am J Hum Genet

    (2006)
  • A.K. Srivastava et al.

    SIZN1 — a new gene implicated in non-syndromic X-linked mental retardation [abstract]

  • R. Ensenauer et al.

    Clinical variability in 3-hydroxy-2-methylbutyryl-CoA dehydrogenase deficiency

    Ann Neurol

    (2002)
  • C. Lenski et al.

    X-linked mental retardation, choreoathetosis and abnormal behaviour (MRXS10) are caused by aberrant splicing in the HADH2 gene

  • E. Reyniers et al.

    A new neurological syndrome with mental retardation, choreoathetosis, and abnormal behavior maps to chromosome Xp11

    Am J Hum Genet

    (1999)
  • Cited by (134)

    • Epigenetics of X-chromosome Inactivation

      2022, Handbook of Epigenetics: The New Molecular and Medical Genetics, Third Edition
    • The role of ISWI chromatin remodeling complexes in brain development and neurodevelopmental disorders

      2018, Molecular and Cellular Neuroscience
      Citation Excerpt :

      They can be broadly subdivided into disorders with intellectual disability/developmental delay (ID/DD), autism spectrum disorders (ASD), and neuropsychiatric disorders; although cohort sequencing combined with phenomics is suggesting that these classifications may constitute arms within a larger disease spectrum with many clinical comorbidities and a significant convergence of genetic pathways (Kochinke et al., 2016). Indeed, the use of exome and whole genome sequencing on large patient cohorts has resulted in the identification of many new causative genes in the past decade for ID/DD and ASD, further facilitating the identification of genetic networks critical for cognition (de la Torre-Ubieta et al., 2016; Kleefstra et al., 2014; Kochinke et al., 2016; Ropers, 2006; van Bokhoven, 2011). A recent compilation has indicated that there are approximately 750 genes identified that contribute to intellectual disability upon mutation (Kochinke et al., 2016).

    • Sex and the Developing Brain

      2015, Sex Differences in the Central Nervous System
    • MicroRNA-222 regulates MMP-13 via targeting HDAC-4 during osteoarthritis pathogenesis

      2015, BBA Clinical
      Citation Excerpt :

      Recent studies have shown that miRNAs play crucial roles in immune cell development and immune system function [17,18] and regulate various aspect of cell physiology, including developmental timing, cell differentiation, apoptosis, and anti-viral defense [18–20]. Given the crucial role of miRNAs in human physiology, the abnormal expression of specific miRNAs may lead to the development of diverse diseases, such as cancer, cardiovascular disorders, mental disorders, musculoskeletal disorders, and lung diseases [21–25]. Recently, intensive research has focused on delineating the roles of various miRNAs in the development of inflammatory and immune-mediated diseases.

    • XLMR protein related to neurite extension (Xpn/KIAA2022) regulates cell-cell and cell-matrix adhesion and migration

      2013, Neurochemistry International
      Citation Excerpt :

      Several genes have been identified as members of the X-linked mental retardation (XLMR) family (Ropers, 2006).

    View all citing articles on Scopus
    View full text