Genetics of X‐linked Mental Retardation

Małgorzata Zofia Lisik, Medical University of Silesia, Poland

Published online: November 2010

DOI: 10.1002/9780470015902.a0020231

X-linked mental retardation (XLMR) refers to a group of inherited disorders characterised by varying degrees of mental retardation, caused by mutations in various genes present on the X-chromosome. Historically, XLMR is divided into syndromic (MRXS) and nonsyndromic (MRX). At least 209 different XLMR disorders have been described including 143 forms of syndromic mental retardation. Fragile X syndrome is the most frequent syndrome and most studied XLMR syndrome. It is now possible to identify 42% of the genetic defects in XLMR families with obligate female carriers. Most of the mutated genes in XLMR are thought to influence development, cell migration, formation and maintenance of neural networks and cell-to-cell communication in brain. Thus the diagnosis of mental retardation in a child has an enormous impact in most affected families. Genetic counselling is strongly recommended to family members.

Key Concepts:

  • X-linked mental retardation (XLMR) is a very heterogeneous set of conditions responsible for a large proportion of inherited mental retardation.
  • XLMR can be divided into syndromic (MRXS) and nonsyndromic (MRX).
  • Genes involved in XLMR influence development, cell migration, formation and maintenance of neural networks and cell-to-cell communication in brain.
  • Mental retardation phenotype can emerge as the final common pathway of many different types of abnormal cellular processing.
  • Genetic counselling is an important part in general management in the case of mental retardation.

Keywords: X-linked mental retardation; syndromic X-linked mental retardation; nonsyndromic X-linked mental retardation; fragile X syndrome; recurrence risk; genetic counselling

Figure 1. The location of the 72 genes for XLMR syndromes which have been cloned and mutations demonstrated. Copyright Greenwood Genetic Center, updated July 2010.
Figure 2. The location of the 19 MRX genes and the 17 genes that cause MRX and MRXS. Copyright Greenwood Genetic Center, updated July 2010.
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 References
    van Aelst L and D'Souza-Schorey C (1997) Rho GTPases and signaling networks. Genes & Development 11: 2295–2322.
    book American Psychiatric Association (1994) Diagnostic and Statistical Manual of Mental Disorders DSM-IV. Washington: American Psychiatric Association.
    Bienvenu T, des Portes V, Saint Martin A et al. (1998) Non-specific X-linked semidominant mental retardation by mutations in Rab GDP-dissociation inhibitor. Human Molecular Genetics 7: 1311–1315.
    de Brouver AP, Yntema HG, Kleefstra T et al. (2007) Mutation frequencies of X-linked mental retardation genes in families from the EuroMRX consortium. Human Mutation 28: 207–208.
    Chelly J (1999) Breakthroughs in molecular and cellular mechanisms underlying X-linked mental retardation. Human Molecular Genetics 10: 1833–1838.
    Chelly J and Mandel JL (2001) Monogenic causes of X-linked mental retardation. Nature Reviews. Genetics 2: 669–680.
    Chiurazzi P, Tabolacci E and Neri G (2004) X-linked mental retardation (XLMR): from clinical conditions to cloned genes. Critical Reviews in Clinical Laboratory Services 41: 117–158.
    Couvert P, Bienvenu T, Aquaviva C et al. (2001) MECP2 is highly mutated in X-linked mental retardation. Human Molecular Genetics 10: 941–946.
    Crow YJ and Tolmie JL (1998) Recurrence risks in mental retardation. Journal of Medical Genetics 35: 177–182.
    Curry JC, Stevenson RE, Aughton D and Byrne J (1997) Evaluation of mental retardation: recommendations of consensus conference. American Journal of Medical Genetics 7: 468–477.
    Froyen G, Bauters M, Voet T et al. (2006) X-linked mental retardation and epigenetics. Journal of Cellular and Molecular Medicine 10: 808–825.
    Froyen G, van Esch H, Bauters M et al. (2007) Detection of genomic copy number changes in patients with idiopathic mental retardation by High-Resolution X-Array-CGH: important role for increased gene dosage of XLMR genes. Human Mutation 28: 1042–1043.
    Gecz J and Mulley J (2000) Genes for cognitive function: developments on the X. Genome Research 10: 157–163.
    Gecz J, Shoubridge C and Corbett M (2009) The genetic landscape of intellectual disability arising from chromosome X. Trends in Genetics 25: 308–316.
    book Hagerman RJ (2002) "The physical and behavioural phenotype". In: Hagerman RJ and Fragile X (eds) Syndrome: Diagnosis, Treatment and Research. Baltimore, MD: Johns Hopkins University Press.
    Hall A (1998) Rho GTP-ases and the actin cytoskeleton. Science 279: 509–514.
    Herbst DS and Miller JR (1980) Nonspecific X-linked mental retardation II: the frequency in British Columbia. American Journal of Medical Genetics 7: 461–469.
    Higgins JJ and Topaloglu H (2005) X-linked oligophrenic vermian dysgenesis: syndromic vs non-syndromic X-linked mental retardation? Neurology 65: 1346–1347.
    Ishizaki H, Miyoshi J, Kamiya et al. (2000) Role of Rab GDP dissociation inhibitor in regulating plasticity of hippocampal neurotransmission. Proceedings of the National Academy of Sciences of the USA 97: 1587–1592.
    Jamain S, Quach H, Betancur C et al. (2003) Mutations of the X-linked genes encoding neuroligins NLGN3 and NLGN4 are associated with autism. Nature Genetics 34: 27–29.
    Jensen LR, Lenzner S, Moser B et al. (2007) X-linked mental retardation: a comprehensive molecular screen of 47 candidate genes from a 7,4 interval in Xp11. European Journal of Human Genetics 15: 68–75.
    Kato M, Das S, Petras K et al. (2004) Mutations of ARX are associated with striking pleiotropy and consistent genotype-phenotype correlation. Human Mutation 23: 147–159.
    Kerr B, Turner G, Mulley J et al. (1991) Non-specific mental retardation. Journal of Medical Genetics 28: 378–382.
    Kleefstra T and Hamel BCJ (2005) X-linked mental retardation: further lumping, splitting and emerging phenotypes. Clinical Genetics 67: 451–467.
    Landomeri M and Dellaire G (2002) Multifunctional zinc finger proteins in development and disease. Annals of Human Genetics 66: 33–42.
    Laumonnier F, Cuthbert PC and Grant GN (2007) The role of neuronal complexex in human X-linked brain diseases. American Journal of Human Genetics 80: 205–220.
    Lehrke RG (1974) X-linked mental retardation and verbal disability. Birth Defects 10: 1–100.
    Leonard H and Wen X (2002) The epidemiology of mental retardation: challenges and opportunities in the new millennium. Mental Retardation and Developmental Disabilities Research Reviews 8: 117–134.
    Lugtenberg D, Veltman JA and van Bokhoven H (2007) High-resolution genomic microarrays for X-linked mental retardation. Genetics in Medicine 9: 560–565.
    Lugtenberg D, Yntema HG, Banning MJG et al. (2006) ZNF674: a new Kruppel-associated box-containing zinc-finger gene involved in non-syndromic X-linked mental retardation. American Journal of Medical Genetics 78: 265–278.
    Merienne K, Jouquot S, Pannetier S et al. (1999) A missense mutation in RPS6KA3 (RSK2) responsible for non-specific mental retardation. Nature Genetics 22: 13–14.
    Muller BM, Kistner U, Kindler S et al. (1996) SAP102, a novel post synaptic protein that interacts with NMDA complexes in vivo. Neuron 17: 255–266.
    Nokelainen P and Flint J (2002) Genetic effects on human cognition: lessons from the study of mental retardation syndromes. Journal of Neurology, Neurosurgery, and Psychiatry 72: 287–296.
    book Nussbaum RL and Ledbetter DH (1995) "The fragile X syndrome". In: Scriver CR, Beaudet AL, Sly WS and Valle D (eds) The Metabolic and Molecular Bases of Inherited Disease, pp. 795–810. New York: McGraw Hill Inc.
    book Penrose LS (1938) A Clinical Study and Genetic Study of 1280 Cases of Mental Defect, vol. 229. London: HM Stationary Office Privy Council of Medical Research Council.
    Petrij F, Giles RH, Dauwerse HG et al. (1995) Rubinstein-Taybi syndrome caused by mutations in the transcriptional co-activator CBP. Nature 376: 348–351.
    Philip N, Chabrol B, Lossi AM et al. (2003) Mutations in the oligophrenin-1 gene (OPHN1) cause X linked congenital cerebellar hypoplasia. Journal of Medical Genetics 40: 441–446.
    Renieri A, Pescucci C, Longo I et al. (2005) Non-syndromic X-linked mental retardation: from a molecular to a clinical point of view. Journal of Cellular Physiology 204: 8–20.
    Ropers HH and Hamel BCJ (2005) X-linked mental retardation. Nature Reviews. Genetics 6: 46–57.
    Ropers HH, Hoeltzenbein M, Kalscheuer V et al. (2003) Nonsyndromic X-linked mental retardation: where are the missing mutations? Trends in Genetics 19: 316–321.
    Ross MT, Grafham DV, Coffey AJ et al. (2005) The DNA sequence of the human X chromosome. Nature 434: 325–337.
    Salomons GS, van Dooren SJ, Verhoewen NM et al. (2003) X-linked creatine transporter defect: an overview. Journal of Inherited Metabolic Disease 26: 309–318.
    Schoichet SA, Hoffman K, Menzel C et al. (2003) Mutations in the ZNF41 gene are associated with cognitive deficits: Identification of a new candidate for X-linked mental retardation. American Journal of Human Genetics 73: 1341–1354.
    Stevenson RE (2000) Splitting and lumping in the nosology of XLMR. American Journal of Medical Genetics 97: 174–182.
    Stromme P, Mangelsdorf M, Shaw M et al. (2002) Mutations in the human ortholog of aristaless cause X-linked mental retardation and epilepsy. Nature Genetics 30: 441–445.
    Trivier E, De Cesare D, Jacquot S et al. (1996) Mutations in the kinase Rsk-2 associated with Coffin-Lowry syndrome. Nature 384: 567–570.
    Turner G and Partington M (2000) Recurrence risk in undiagnosed mental retardation. Journal of Medical Genetics 31: 45–47.
    Wang Ye, Esbensen P and Bentley D (1998) Arginine kinase expression and localisation in growth cone migration. Journal of Neuroscience 18: 987–998.
    Yntenema H, Poppelaars F, Derksen E et al. (2002) Expanding phenotype of XNP mutations: Mild to moderate mental retardation. American Journal of Medical Genetics 110: 243–247.
 Further Reading
    Raymond FL (2006) X linked mental retardation: a clinical guide. Journal of Medical Genetics 43: 193–200.
    Ropers HH (2008) Genetics of intellectual disability. Current Opinion in Genetics and Development 18: 241–250.
    Stevenson RE and Schwartz CE (2009) X-linked intellectual disability: unique vulnerability of the male genome. Developmental Disabilities Research Reviews 15: 361–368.
 Web Links
    ePath http://www.ncbi.nlm.nih.gov/Omim/mimstats.html
    ePath http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db
    ePath http://www.ensembl.org
    ePath http://www.ggc.org/xlmr.htm
    ePath http://xlmr.interfree.it

Related Sub-Topics:

Specific Genetic Disorders | Mutational Mechanisms of Genetic Disease | Techniques and Tools in Clinical Genetics
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Article Title: Genetics of X‐linked Mental Retardation
 
How to Cite close
Lisik, Małgorzata Zofia(Nov 2010) Genetics of X‐linked Mental Retardation. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0020231]