X-linked mental retardation

Key Points

  • X-linked genetic defects are important causes of mental retardation, and recent years have seen important progress in the identification of the genes involved in X-linked mental retardation (XLMR).

  • There are two main forms of XLMR — syndromic XLMR (S-XLMR), which is associated with additional phenotypes, and non-syndromic XLMR (NS-XLMR).

  • Whereas most of the genetic defects that underlie S-XLMR are either known or have been mapped to small chromosomal regions, fewer than 50% of those that underlie NS-XLMR have been identified.

  • Genes that are involved in S-XLMR can be identified using standard techniques for identifying genes involved in monogenic disorders. However, it is not as straightforward for NS-XLMR, mainly because of the genetic heterogeneity of this condition.

  • Recent years have seen concerted efforts to identify genes that are involved in XLMR. Studies of chromosomal rearrangements, the availability of large numbers of families for genetic analysis and large-scale mutational screening have all been important in this work.

  • The identification of XLMR-associated genes has provided insights into brain function. The genes that are affected in these conditions have roles in processes such as neuronal outgrowth, synaptic structure and function, synaptic plasticity and learning and memory, and might also be determinants of intelligence.

  • Polymorphisms that predispose to mental retardation — but are not sufficient to cause symptoms on their own — might be present within the protein-coding regions of genes, their regulatory regions or in genes that encode small regulatory RNAs. Allelic variants of genes that are involved in XLMR might be candidates for such polymorphisms.

  • Understanding the genetic causes of XLMR will be important in developing diagnostic, preventive and therapeutic strategies for the treatment and management of this condition.

Abstract

Genetic factors have an important role in the aetiology of mental retardation. However, their contribution is often underestimated because in developed countries, severely affected patients are mainly sporadic cases and familial cases are rare. X-chromosomal mental retardation is the exception to this rule, and this is one of the reasons why research into the genetic and molecular causes of mental retardation has focused almost entirely on the X-chromosome. Here, we review the remarkable recent progress in this field, its promise for understanding neural function, learning and memory, and the implications of this research for health care.

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Figure 1: Identification of genes that are involved in non-syndromic cases of X-linked mental retardation (NS-XLMR).
Figure 2: Chromosomal rearrangements: clues to the identity of X-linked mental retardation (XLMR) genes.

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Acknowledgements

We thank C. E. Schwartz and R. Stevenson (Greenwood), A. Meindl, J. Ramser and E. Holinski-Feder (München), G. Turner and M. Partington (Newcastle, Australia) as well as all members of the EURO-MRX Consortium for sharing with us information about linkage intervals and mutations identified in families with NS-XLMR. Thanks are also due to R. Plomin and I. Craig (London), J.-L. Mandel (Strasbourg), A. Bird (Edinburg) and colleagues from our own institutions for allowing us to cite their unpublished results or work that is in the press; to H. Markert and V. Kalscheuer for their help with the preparation of the manuscript and figures; and to J. Gecz (Adelaide) for his comments on an early version of this review.

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Correspondence to H.-Hilger Ropers.

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DATABASES

Entrez

FMR1

FMR2

CDKL5

ARX

ACSL4

PQBP1

FTSJ1

ZNF41

PHF8

DLG3

OPHN1

PAK3

MECP2

RSK2

OMIM

Fragile X syndrome

Rett syndrome

Epilepsy, female restricted, with mental retardation

FURTHER INFORMATION

e! project ENSEMBL MartView

European XLMR Consortium

Greenwood Genetic Centre — XLMR update

Max Planck Institute for Molecular Genetics — Nonsyndromic X-linked mental retardation

XLMR Genes Update

Glossary

BALANCED REARRANGEMENTS

Chromosomal rearrangements that change the chromosomal gene order but do not remove or duplicate any of the DNA from the chromosomes. The two most simple classes of balanced rearrangements are inversions and reciprocal translocations.

DENDRITE

A branching extension from the cell body that receives synaptic input from the axon of another neuron.

RNA-INDUCED SILENCING COMPLEX

A multi-component, ribonucleoprotein complex that cleaves specific mRNAs that are targeted for degradation by homologous dsRNAs during the process of RNA interference.

NEURITE

Any process that extends from the cell body of the neuron, such as the dendrite or axon.

RHO GTPases

A family of small GTPases that are components of a number of signal-transduction pathways.

DENDRITIC SPINES

Specialized regions of the dendrite that receive synaptic inputs from other neurons.

POSTSYNAPTIC DENSITY PROTEIN

An electron-dense thickening of the postsynaptic membrane that contains a high concentration of neurotransmitter receptors, scaffolding proteins and signalling molecules.

EVH1 DOMAIN

First identified in the Ena/VASP family of proteins in Drosophila melanogaster, EVH1 domains bind poly-proline rich regions that are recognized by various binding partners.

SYNAPTIC PLASTICITY

A change in the functional properties of a synapse as a result of use.

DENSE-CORE GRANULE

Large diameter (80–200 nm) secretory vesicles that have high electron density when visualized by electron microscopy. They usually contain neuropeptides or catecholamines (hormones that affect the sympathetic nervous system).

ATAXIA

Inability to coordinate movement.

ANGELMAN-LIKE SYNDROME

A genetic disorder that is caused by deletion or disruption of UBE3A (E6-AP). The symptoms of Angelman syndrome include hyperactivity, ataxia, problems with speech and language, and an unusually happy demeanour.

PRADER–WILLI-LIKE SYNDROME

A genetic disorder that is caused by loss of gene function on chromosome 15. Features of the disorder include excessive eating (hyperphagia), obesity, short stature, mental retardation or learning disabilities, and behavioural problems.

OSTEOBLAST

A mesenchymal cell with the capacity to differentiate into bone tissue.

HOMEODOMAIN FINGERS

A highly conserved sequence motif, usually comprising 60 amino acids, that includes a DNA-binding region.

TWO PHOTON IMAGING

A form of imaging in which a fluorochrome that would normally be excited by a single photon is stimulated quasi-simultaneously by two photons of lower energy. This allows reduced light scattering and less photodamage of the sample.

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Ropers, HH., Hamel, B. X-linked mental retardation. Nat Rev Genet 6, 46–57 (2005). https://doi.org/10.1038/nrg1501

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