genetica disabilitatilor intelectuale

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Intellectual Disability:GeneticsSamantha JL Knight, Oxford Partnership Comprehensive Biomedical Research Centre,

Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK

Based in part on theprevious version of this Encyclopediaof Life Sciences (ELS) article, Intellectual Disability by Jonathan Flint.

The extent to which genetics plays a role in intelligence has long been a matter for

debate. However, it is now well established that genetic effects can contribute to

intellectual disability (ID), in particular, moderate to severe ID. The discovery of

chromosomal rearrangements and the cloning of causal genes have both clinical and

scientific value. Clinically, they help the families of those affected by providing

molecular diagnoses, alleviating feelings of guilt and allowing more accurate genetic

counselling. Scientifically, they provide important clues regarding the underlying

biology of cognition.

Introduction

The extent and nature of a genetic contribution to intel-ligence has been a contentious subject for many years,largely centred on arguments about the validity and inter-pretation of intelligence quotient (IQ) tests. Psychometricassessment of intelligence began at the turn of the last cen-tury, and in most tests the items used are age-adjusted andassembled to give a normal distribution with a mean of 100

and a standard deviation of approximately 15 units. IQscoreslower than 70 aremore than twostandard deviationsfrom the mean and are conventionally regarded as indica-

tors of mental retardation (MR), learning disability (LD)or intellectual disability (ID).

When the tests were first introduced,it wasobservedthatthelow endof theIQ spectrum included toomany people tofit a normal distribution. In 1914, Pearson, a British mathe-matician, and Jaderholm, a Swedish psychologist, pro-posed that the IQ distribution was a combination of twodifferent populations, the excess at the lower end arisingfrom mechanisms separate from those contributing to the

bulk of the normally distributed IQ range (Figure 1). Sub-sequently the view has emerged that there are two types of genetic contribution to ID: in most cases a low IQ is theresult of the action of multiple genes (polygenes), each of small and additive effect, that contribute to the normal

variation in intellectual capacity (this is the standard bio-metric model of polygenic action). The second type of ge-netic contribution is pathological because it is theconsequence of an abnormality in the number or make-up of chromosomes, including abnormal changes (muta-tions) in genes critical for the development and completeexpression of intelligence. The latter pathological contri-bution is considered responsible for a much smaller pro-portion of LD cases than polygenes but almost all have an

IQ of less than 50.Table 1 summarizes the causes of ID obtained from

epidemiological and scientific studies of low IQ, followingthe convention of separating mild disability (IQ 50–70)from moderate to severe disability (IQ550). Overall theresults reveal a distinction between the two groups. Formoderate to severe disability, genetic and chromosomalabnormalities are a major cause. Indeed, Down syndrome(caused by an additional chromosome 21) and X-linkedMR (XLMR) have been recognized as major single

F r e q u e n c y

0 50 100 150

IQ score

Figure 1 Two-group hypothesis of intellectual disability. The explanation

fortheexcess oflow intelligence quotient(IQ) is shownas anadditionalcurvesuperimposed to the left of a normal distribution that has its mean at 100.

Advanced article

Article Contents

. Introduction

. Inherited Forms of Intellectual Disability

.

SingleGeneMutationsCausing IntellectualDisability andFunctional Effects

. Genome Imbalance in Intellectual Disability

. Polygenic Studies of Intellectual Disability

. Conclusion

. Acknowledgements

Online posting date: 15th December 2008

ELS subject area: Genetics and Disease

How to cite:

Knight, Samantha JL (December 2008) Intellectual Disability: Genetics.In: Encyclopedia of Life Sciences (ELS). John Wiley & Sons, Ltd:Chichester.

DOI: 10.1002/9780470015902.a0005515.pub2

ENCYCLOPEDIA OF LIFE SCIENCES& 2008, John Wiley & Sons, Ltd. www.els.net 1



contributors for many years. In the late 1990s, small chro-mosomal rearrangements affecting the ends (telomeres) of chromosomes also emerged as a common cause, found in

7% cases previously regarded as idiopathic (Knight, 2005).However, since this time, technology has advanced rapidlyand it is now emerging that small chromosomal gains andlosses (referred to as genomic imbalances, segmental an-eusomies or copy number variants (CNVs)) that occur

throughout the genome (not just telomeres) account for amajor proportion of previously undiagnosed individuals,currently providing approximately 7–12% additional mo-lecular diagnoses in moderate to severe ID.In the futureit islikely that there will be considerably morecases of unknownaetiology for which a genetic origin will be discovered.

The genetic picture for those with mild ID is less clear.The importance of polygenic influences is inferred from theresults of twin, family and adoption studies for normal IQmeasures, rarely from direct investigation of families withlow IQ (studies evaluating biological and environmentalrisk factors in this group are singularly lacking). However,there are indications that single gene conditions may be

more frequent than previously assumed. In addition, clin-ically relevant interstitial CNVs are now being reported,currently accounting for approximately 3–5% mild IDcases; the exact figure is difficult to ascertain because few

studies make a distinction between the mild and moderateto severe IQ groups.

Inherited Forms of IntellectualDisability

For many years the study of the effect of single gene dis-orders on intellectual function was restricted to the analysis

of metabolic conditions, which are now generally believedto give rise to ID as a secondary complication; the meta-bolic defect results in abnormal quantities of metabolites in

the brain. This situation changed with the advent of mo-lecular cloning, making it possible to investigate the geneticbasis of other Mendelian disorders where there might be adirect causal relationship between ID and genetic defect.Broadly speaking, these disorders can be divided into

syndromic and nonsyndromic forms. In the former, thepatients with ID display additional physical, behaviouralor neurological symptoms whereas in the latter, ID is theonly clinical manifestation. However, the clinical bound-ary between the two categories is gradually becomingblurred, mainly because of increasing numbers of examplesof single genes in which mutations are associated with bothsyndromic as well as nonsyndromic forms (e.g. mutationsin PQBP1, RSK2, XNP, ARX , MECP2, OPHN1, FMR1),indicating allelism.

In the following sections, nonsyndromic and syndromicintellectual disabilities are discussed with the initial focusbeing on known single gene disorders and the functional

effects of the mutations. Next, genome imbalances andCNVs are discussed and, finally, polygenic effects areconsidered.

Single Gene Mutations CausingIntellectual Disability and FunctionalEffects

Tables 2 – 4 list, respectively, many of the single genes cur-

rently known to cause nonsyndromic and syndromic ID.Of these, most are on the X-chromosome, underscoring

Table 1 Summary of the most common causes of intellectual disability

% Cases attributable to cause

Aetiological cause IQ less than 50 IQ between 50 and 70

Genetic 58–63 13–15

Down syndrome 33 5Other autosomal aneuploidy 2 1

Sex chromosome aneuploidy 51 1

Subtelomeric rearrangements 7 51

Interstitial submicroscopic CNVs 7–12 3–5

Fragile X syndrome 2 51

Single gene disorder 6 2

Environmental 19 10

Prenatal 4 3

Perinatal 10 4

Postnatal 5 3

Unknown 18–23 75–77

The contribution of each aetiological cause is shown as a percentage of the total for two degrees of intellectual disability, moderate to severe(IQ 550) and mild (IQ between 50 and 70). CNV, copy number variant.

Intellectual Disability: Genetics

ENCYCLOPEDIA OF LIFE SCIENCES& 2008, John Wiley & Sons, Ltd. www.els.net2



Table 2 Examples of single genes implicated directly in the cause of nonsyndromic intellectual disability

Disorder Location Gene Proposed function of protein

NS-XLMR Xp22.2-p22.1 RSK2

(RPS6KA3)

Serine threonine protein kinase that phosphorylates CREBBP

and regulates histone H3 acetyltransferase, to play a role in

learning, long-term memory, synaptic transmission and

neuronal survival.

NS-XLMR Xp22.13 ARX Homeobox protein; transcriptional regulator.

NS-XLMR Xp22 AP1S2 Assembly of endocytic vesicles.

NS-XLMR Xp21.2-21.3 IL1RAPL1 Negative regulator that may help modulate synaptic

neurotransmitter release.

NS-XLMR Xp11.3 ZNF41 Transcriptional regulation through chromatin remodelling.

NS-XLMR Xp11.3 ZNF674 Transcriptional regulation through chromatin remodelling.

NS-XLMR Xp11.23 FTSJ1 Ribonucleic acid (RNA) methyltransferase modifying

untranslated RNAs, thereby playing a critical role in protein

translation.NS-XLMR Xp11.23 ZNF81 Transcriptional regulation through chromatin remodelling.

NS-XLMR Xp11.23 PQBP1 Polyglutamine tract binding protein gene; transcriptional co-

activator.

NS-XLMR Xp11.22 FGD1 Rho GTPase Cycle: GDP–GTP exchange factor that affects

formation and dismantling of actin cytoskeleton.

NS-XLMR Xq11 TM4SF2 Modulates beta-1 integrins-mediated signalling to play a role

in neurite outgrowth and synapse formation and control of

neurite growth.

NS-XLMR Xq12 OPHN1 Rho GTPase cycle GDP–GTP exchange factor: negatively

regulates formation and dismantling of actin cytoskeleton andcontrol of axon and dendrite growth.

NS-XLMR Xq13 BRWD3 Involved in intracellular signalling pathways affecting cellular

proliferation.

NS-XLMR Xq13.1 DLG3

(SAP102)

Links neuroligins to N -methyl-D-aspartate (NMDA)-type

glutamatergic receptors affecting NMDA receptor-mediated

synaptic activity and plasticity.

NS-XLMR Xq22.3 FACL4 Long-chain fatty acid metabolism, thought to regulate the

availability of eicosapentaenoic acid (EPA), and omega-6

arachidonic acid (AA), important for neuronal function.

NS-XLMR Xq23 PAK3

(OPHN3)

Rho GTPase cycle: a downstream effector linking Rho GTPases

to actin cytoskeleton and MAPK cascades involved in

neurodegeneration, cell differentiation and proliferation.

NS-XLMR Xq26.3 ARHGEF6 Rho GTPase cycle GDP–GTP exchange factor: positively

regulates formation and dismantling of actin cytoskeleton and

control of neurite growth.

NS-XLMR Xq27.3 FMR1 RNA binding protein with role in synaptic maturation and

function, and in germ cell proliferation.

NS-XLMR Xq28 FMR2 Nuclear transcriptional regulator with role in memory and

learning. Needed for normal long-term synaptic plasticity in

the hippocampus?

(Continued )





the fact that the vast majority of recognized Mendelian IDis X-linked. This is because X-linked recessive disease is

compatible with affected members existing in multiple gen-erations; it is therefore both recognizable as an inheritedcondition and amenable to genetic mapping. XLMR is alsocommon: the frequency is estimated to be 1.8 in 1000 maleswith a carrier frequency of 2.4 in 1000 females (Glass,1991). To date, there are over 270 recorded XLMR con-

ditions and more than 70 causative genes have been iden-tified. In contrast, very little is known about the role of autosomal genes, even though their contribution to ID mayturn out to be more common. To date, five genes have beenimplicated in nonsyndromic autosomal-recessive forms of MR (NS-ARMR) and eight genes in syndromic autosomalMR (S-AMR). See also: X-linked Genes for General

Cognitive AbilitiesID can result from a wide range of protein abnormal-

ities. However, it is emerging that a number of the caus-

ative single genes identified can be linked throughbiochemically related gene products. There are at leastfour identifiable pathways to date: (a) signalling net-works that use Rho GTPase proteins, (b) transcriptionalregulation through transcription factors, (c) transcrip-tional regulation through chromatin remodelling and(d) genes associated with chemical synapses, synapticvesicles and synaptic plasticity (Figure 2). A fifth groupmay include genes linked to RNA splicing, proteintranslation or degradation or that those having a role inenergy metabolism.

Signalling networks that use Rho GTPaseproteins

There are six genes on the X-chromosome that involve sig-nalling networks of the Rho GTPase cycle. Rho GTPasesregulate vesicle trafficking of molecules between mem-brane-bound organelles in eukaryotic cells by reversiblyassociating with lipid membranes (Figure 2a). Rho proteinsactivated by GDP (guanosine diphosphate)-GTP (guano-sine triphosphate) exchange factors (GEFs) become asso-ciated with membranes, the rate of GDP–GTP conversiondepending on the particular GEF. They are inactivated(extracted from membranes and maintained in the cytosol)by binding to GDP-dissociation inhibitor (GDI). Deliveryof Rho GTPases to sites of activation involves their release

from GDI and is thought to require GDI-displacementfactors (GDFs). Of the XLMR genes involved in this net-work, FGD1 acts as a cdc42-specific GEF, ARHGEF6 is aGEF that positively regulates Rho GTPase and OPHN1

and GDI1 (OPHN2) areGEFs that negatively regulate RhoGTPase; all are implicated in the formation and dis-mantling of the actin cytoskeleton and the control of axonand dendrite growth. Similarly, mutations of the G-protein-coupled receptor encoded by AGTR2 are thoughtto disturb Rho signalling, resulting in degenerationof the dendritic cytoskeleton. PAK3, or P21 activated

kinase (OPHN3), is a critical downstream effector that linksRho GTPases to the actin cytoskeleton and to mitogen-activated protein kinase (MAPK) cascades involved in

Table 2 Continued

Disorder Location Gene Proposed function of protein

NS-XLMR Xq28 GDI1

(OPHN2)

Rho GTPase cycle GDP–GTP exchange factor: negatively

regulates formation and dismantling of actin cytoskeleton and

control of neurite growth.

NS-XLMR Xq28 MECP2 Regulates transcription by binding methylated CpG dimer

pairs leading to chromatin decondensation.

NS-ARMR;

MRT2

3p26.2 CRBN Putative signal transducer that plays a role in neurotrophin-

regulated signalling pathways affecting neuron development,

survival and function.

NS-ARMR;

MRT1

4q26 PRSS12 Extracellular multidomain serine protease located in cortical

synapse presynaptic nerve endings and associated with neural

development and plasticity.

NS-ARMR 6q21 GRIK2 Kainate receptor subunit involved in synaptic transmission.

NS-ARMR 8p22 TUSC3 Subunit of the endoplasmic reticulum-bound

oligosaccharyltransferase complex. May catalyse a pivotalstep in protein N -glycosylation (?).

NS-ARMR;

MRT3

19p13.12 CC2D1A Regulates endocytosis and required for endosomal trafficking of

Notch (single-pass transmembrane receptor that regulates cell

fate decisions during development).



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Table 3 Examples of single X-linked genes implicated directly in the cause of syndromic intellectual disability

Category of

disorder and name Location Gene Proposed function of protein

S-XLMR; autism Xp22.33 NLGN4 Neuronal cell surface protein located at synaptic

structures.

S-XLMR; Coffin–

Lowry syndrome

Xp22.2-p22.1 RSK2

(RPS6KA3)

Serine threonine protein kinase that phosphorylates

CREBBP and regulates histone H3 acetyltransferase, to

play a role in learning, long-term memory, synaptic

transmission and neuronal survival.

S-XLMR; OpitzG/

BBB

Xp22.2 MID1 Microtubule-associated protein important for midline

structure development. Spliced or truncated forms may

confer different pathogenicity in the brain (?).

S-XLMR Xp22.13 ARX Transcription factor with a role in neuronal proliferation

and differentiation.

S-XLMR Xp11.3 SYN1 Effector of small Ras-like GTPase, Rab3A, on small

synaptic vesicles.S-XLMR;

Renpenning

syndrome,

Golabi–Ito–Hall

syndrome, Hamel

cerebro-palato-

cardiac syndrome,

Sutherland–Haan

syndrome,

Porteous

syndrome

Xp11.23 PQBP1 Polyglutamine tract binding protein gene; transcriptional

co-activator.

S-XLMR Xp11.22-11.21 JARID1C (SMCX)

Transcriptional repressor; chromatin dynamics andREST-mediated neuronal gene regulation.

S-XLMR;

Siderius–Hamel

Cleft lip and palate

syndrome

Xp11.22 ZNF422 (PHF8) PHD finger protein family of transcriptional regulators

affecting gene expression by chromatin remodelling.

Putative role in midline formation and in the development

of cognitive abilities.

S-XLMR; Stocco

dos Santos

syndrome

Xp11.2 SHROOM4 Regulates cytoskeletal architecture?

S-XLMR; ATR-X

syndrome,

MRXHF1

Xq21.1 ATRX (XNP) Abnormal methylation – transcriptional regulator.

Member of the SWI/SNF family of chromatin remodelling

proteins crucial for normal development and organizationof the brain’s cortex.

S-XLMR;

Duchenne

muscular

dystrophy

Xp21.2 DMD Localizes to synapses. Regulates neurotransmitter

release?

S-XLMR; Mild

Cornelia de Lange

syndrome

Xp11.22 SMC1A Involved in cohesin association with and dissociation from

chromosomes.

S-XLMR Xq12 OPHN1 Rho GTPase cycle: negative regulation affects formation

and dismantling of actin cytoskeleton and control

of axon and dendrite growth.(Continued )





neurodegeneration, cell differentiation and proliferation.Thus, all of these genes implicated in the Rho GTPasecycle most likely have a primary effect on the developmentand maintenance of intellectual function through thecontrol of axon and dendrite growth in the brain.

Transcriptional regulation throughtranscription factors

Transcription is the conversion of genetic information

from DNA (deoxyribonucleic acid) to mRNA (messen-ger ribonucleic acid), activated by the enzyme RNA

polymerase. The overall process is highly regulatedrequiring other proteins to produce the transcriptand to ensure the correct spatio-temporal expression of genes. Proteins known as transcription factors achievethis alone, or by using other regulatory proteins in acomplex, activating or repressing the presence of RNApolymerase (Figure 2b). Some transcriptional regulatorsinteract specifically with the core transcription machinerywhereas others function through modification of the

local chromatin environment (see later). Genes encod-ing transcription factors or transcription regulatorsthat interact with them and implicated in ID includeTBX1, ARX and PQBP1. TBX1 maps to the 22q11.2

Table 3 Continued

Category of

disorder and name Location Gene Proposed function of protein

S-XLMR;

Opitz–Kaveggia

syndrome; FGsyndrome;

Lujan–Fryns

syndrome

Xq13.1 MED12 Mediator of RNA polymerase II transcription. Key role in

the mediator complex (essential for transcriptional

regulation); directly modulates receptor tyrosine kinase,nuclear receptor and Wnt pathway signalling.

S-XLMR Xq23 AGTR2 (AT2) G-protein-coupled receptor with possible role in Rho

GTPase cycle affecting the integrity of the dendritic

cytoskeleton. Mutations may affect brain development,

memory and learning. May also have a role in

cardiovascular functioning.

S-XLMR Xq24 CUL4B Ubiquitin E3 ligase subunit. Member of cullin protein

family that function primarily as scaffold proteins for a

series of ubiquitin-protein ligase complexes that regulate

cellular protein degradation.

S-XLMR Xq24 UBE2A Ubiquitin-conjugating enzyme in the proteasome

pathway of protein degradation. May also control

transcription factor activity, receptor internalization and

chromatin remodelling through histone modification (?).

S-XLMR Xq26.1 ZDHHC9 Palmitoyltransferase that catalyses the posttranslational

modification of RAS. Mutations may alter RAS protein

levels within nerve cell compartments, affecting growth

and development of neurons (?).

S-XLMR;

Borjeson–

Forssman– Lehmann

syndrome

Xq26.3 PHF6 PHD finger protein family of transcriptional regulators

affecting gene expression by chromatin remodelling.

S-XLMR; Fragile

X syndrome

Xq27.3 FMR1 RNA binding protein with role in synaptic maturation and

function, and in germ cell proliferation.

S-XLMR; Rett

syndrome

Xq28 MECP2 Regulates transcription by binding methylated CpG

dimer pairs leading to chromatin decondensation.

S-XLMR Xq28 SLC6A8 Creatine transporter. Involved in exocytotic creatine

release mechanism at synaptic vesicles (?).





microdeletion syndrome region. Deletions involving thisregion cause a variable phenotype, including DiGeorgesyndrome (DGS) and the clinically overlapping velo-cardiofacial syndrome (VCFS). About 97% of patientswith DGS/VCFS have either a common recurrent dele-tion of approximately 3 Mb or a less common, 1.5 Mbnested deletion. Haploinsufficiency of the TBX1 gene isresponsible for most of the physical malformations, butpoint mutations in TBX1 can also cause the disorder(Yagi et al., 2003; Stoller and Epstein, 2005). TBX1 is a

member of T-box containing transcription factor family.In the heart it regulates the balance between myocardial

proliferation and differentiation (Liao et al., 2008). In thebrain, TBX1 mutations may reduce prepulse inhibition, afeature of several psychiatric disorders and consistentwith the intellectual and psychiatric components of the22q11.2 deletion syndrome (Paylor et al., 2006).

ARX is implicated in West syndrome, Partington syn-drome and X-linked lissencephaly with absent corpuscallosum and ambiguous genitalia. It codes for a homeo-box protein which is also a transcriptional regulator.PQBP1 is a polyglutamine tract-binding protein gene for

which mutations have been reported in five XLMR disor-ders (Table2) as well as in other XLMR families. Mutations

Table 4 Examples of single autosomal genes implicated directly in the cause of syndromic intellectual disability

Category of disorder and

name Location Gene Proposed function of protein

S-AMR: Cornelia de

Lange syndrome

5p13.1 SMC1 (NIPBL) Part of cohesin complex that mediates sister

chromatid cohesion to bind to chromosomes.

May regulate cohesin to affect gene expression,meiosis and development (?).

S-AMR: Sotos syndrome;

Weaver syndrome

5q35 NSD1 NR coregulator protein. Modulates the

transcription of nuclear receptor target genes by

participating in chromatin remodelling or

interacting with transcription machinery to affect

the preinitiation complex formation. Crucial in

postimplantation development.

S-AMR: 9q subtelomeric

deletion syndrome

9q34.3 EHMT1 Histone methyltransferase that methylates

H3-K9 histone to silence individual genes. Has

role in carrying out the histone modifications

needed to transfer a subset of the neuronal

precursor cells into the Go phase after cell division.

S-AMR: Mild Cornelia de

Lange syndrome

10q25 SMC3 Part of cohesin complex essential for sister

chromatid adhesion during mitosis. Topologic

association with chromatin (?).

S-AMR: FRA12A 12q13.12 DIP2B May be involved in DNA-methylation

processes (?).

S-AMR: Angelman

syndrome

15q11.2 UBE3A Ubiquitin-conjugating enzyme in the the

proteasome pathway of protein degradation.

S-AMR: Rubenstein–

Taybi syndrome

16p13.1 CREBBP Nuclear transcriptional co-activator; a histone

acetyltransferase that regulates gene expression

by acetylating histones and other transcriptionfactors.

S-AMR: Smith–Magenis

syndrome features (21/30

features)

17p11.2 RAI1 PHD finger protein family of transcriptional

regulators affecting chromatin remodelling.

S-AMR: 22q11.2 deletion

syndrome; features of

DiGeorge syndrome and

conotruncal anomaly face

syndrome/velocardiofacial

syndrome, but ID atypical

of DiGeorge syndrome.

22q11.21 TBX1 Transcription factor involved in the regulation

of developmental processes, including those of

the heart and brain.





(a) Rho GTPase cycle

GDP

GDI

GDF GDP

GTP GDP

GTP

G D I

Effector

ActiveRho GTPase

InactiveRho GTPase

Inactive

Rho GTPase

P

Cytosol Lipid membrane

Gene expression

Cell cycle progression

Cell differentiation

Cytokinesis

Cytoskeletal organization

(b) Transcription factors ( ) and regulators ( )

Repressors Co-activators

DNA

Enhancer Promoter Gene

mRNA

Hormoneresponse element

Generaltranscription factors

TATA

RNA polymerase II

(c) Chromatin remodelling

Gene ‘off ’ HistonesRepressor complex

Inactivechromatin

DNA strandChromatin modification eg.methylation/demethylationacetylation/phosphorylation

complex

Gene ‘on’:transcriptionproceeds

Neurotransmitter bound to receptor

Dendrite Axon

Vesicle containingneurotransmitter Synaptic cleft

(~20 µM)

Direction of nerve impulse

(d) Chemical synapses

Activechromatin

Chemically modified histones

GEF

Nuclear receptors Activators

hormones

RNA polymerase

Figure 2 Processes implicated in intellectual disability. Part (b) adapted from image available at http://www.jenabioscience.com/cms/en/t/browse/

576_transcription_factors.html and reproduced with permission of Jena Bioscience GmBH.




of the WW domain of the PQBP1 protein destroy the tran-scription promoting activity of RNA polymerase II; otherPQBP mutations may also affect the protein’s transcrip-tional co-activator function (Lubs et al., 2006).

Transcriptional regulation throughchromatin remodelling

Chromatin is the complex of DNA and protein that makes

up chromosomes. The major proteins involved in chroma-tin are histone proteins (H1, H2A, H2B, H3 and H4 ineukaryotes), although other chromosomal proteins alsohave prominent roles. The functions of chromatin are topackage DNA within the cell, to strengthen the DNA toallow mitosis and meiosis, and importantly to provide amechanism by which gene expression can be controlled.Chromatin remodelling refers to dynamic structuralchanges to the chromatin that occur throughout the cell-division cycle. These epigenetic changes range from thelocal changes necessary for transcriptional regulation toglobal changes necessary for chromosome segregation.Modifications in chromatin structure that influence genetranscription are achieved mainly by methylation and de-methylation (DNA and proteins) and acetylation andphosphorylation (proteins) (Figure2b). Seealso: ChromatinStructure and Modification: Defects

At least 13 genes implicated in ID have an effect ontranscriptional regulation through chromatin remodelling(RSK2, CREBBP, ATRX , MECP2, PHF6, PHF8

(ZNF422), RAI1, SMCX , ZNF41, ZNF81, ZNF674.

NSD1 and EHMT1). It is not possible to discuss fully thefunctional aspects of each here, but a few examples aredetailed. Further clinical characteristics of named condi-tions canbe found in OnlineMendelian Inheritance in Man(OMIM: http://www.ncbi.nlm.nih.gov/omim/). Two ex-amples that are part of a linked process are RSK2 andCREBBP (encoding cyclic adenosine monophosphate re-sponse element-binding protein). RSK2 is a serine threo-

nine protein kinase that activates, by phosphorylation,CREBBP and histone H3. CREBBP is a transcriptionco-activator that regulates gene expression by acetylatinghistones and other transcription factors (Figure 2b and c).Inthe brain, it is involved in learning, memory and synaptic

transmission, as well as in neuronal survival, differentia-tion and axonal growth. RSK2 mutations give rise to

Coffin–Lowry syndrome and partial RSK2 enzyme defi-ciency can result in a NS-XLMR. CREBBP mutationscause the autosomal Rubenstein–Taybi syndrome.

The ATRX and MECP2 protein products are alsolinked. Pathological changes caused by disrupting their in-teraction are thought to contribute to ID (Nan et al. 2007).ATRX is a member of the SWI/SNF family of chromatinremodelling proteins, crucial for normal development andorganization of the brain’s cortex. The MeCP2 proteinbinds to methylated CpG dimer pairs leading to chromatin

decondensation; specific targets include the brain-derivedneurotrophic factor (important for long-term synaptic

plasticity, learning and memory), and also the Hairy2a

gene (important for neurogenesis). ATRX mutations causeX-linked a-thalassaemia mental retardation syndrome(ATRX) whereas mutations of MECP2 cause Rett syn-drome, a progressive neurological disorder affecting fe-males almost exclusively. MECP2 mutations also cause

other conditions, e.g. severe encephalopathy, progressivespasticity, Angelman and Prader–Willi-like phenotypes

and NS-XLMR.PHF6, PHF8 (ZNF422) and RAI1 all encode nuclear

expressed proteins that have functional zinc-finger-likeplant homeodomain (PHD) fingers. They function astranscriptional regulators affecting gene expression bychromatin remodelling. PHF6 is mutated in Borjeson– Forssman–Lehmann syndrome whereas PHF8 is mutatedin Siderius–Hamel Cleft lip and palate syndrome (Loweretal., 2002; Ropersand Hamel,2005) and is thought to playa role in midline formation and the development of cog-

nitive abilities. RAI1 is mutated or deleted in Smith– Magenis syndrome (SMS), a clinically variable syndromecommonly associated with multiple gene deletions withinchromosomal band 17p11.2. Mutations of RAI1 alonecause phenotypic features consistent with SMS, thoughother deleted genes may contribute to the variable featuresand overall severity (Girirajan et al., 2005).

Finally, mutations in three zinc-finger genes, ZNF41,ZNF81 and ZNF674 have also been described inNS-XLMR (Shoichet et al., 2003; Kleefstra et al., 2004;Lugtenberg et al., 2006). All cluster at the Xp11 region andcontain a Kru ¨ ppel-associated box (KRAB) domain.KRAB-containing zinc-finger proteins are primarily

regulators of transcription (Figure 2b and c). The KRABdomain interacts with the KRAB-associated protein 1(KAP-1) which recruits heterochromatin protein 1 (a non-histone protein) and other proteins to form a multiproteinnuclear receptor (NR) corepressor (N-CoR) complex(Underhill et al., 2000). The complex includes histone-

modifying proteins and mediates heterochromatin forma-tion on a target promoter, resulting in gene silencing. ZNFgenes are critical for cognitive development, but the specificmechanism for this has yet to be elucidated.

Genes associated with chemical synapses,synaptic vesicles and synaptic plasticity

Chemical synapses are specialized junctions through whichneurons signal to each other and to nonneuronal cells(Figure 2d). They are crucial to the biological processes thatunderlie perception and thought. A synaptic vesicle is asmall membrane-bound structure located in the axon ter-minals of neurons. It contains neurotransmitters and re-leases them by exocytosis at the presynaptic terminal intothe synaptic cleft (the gap between the pre- and post-synaptic cells). The vesicles are then recycled and filledagain with neurotransmitter molecules. The tight regula-

tion of this process ensures correct spacial and quantitativeeffects of neurotransmitter release. This, in turn, is essential



http://dx.doi.org/10.1038/npg.els.0006071






for correct synapse functioning and thus normal brainfunction. The ability of a synapse to change in functionand/or in neurotransmitter signal strength is known assynaptic plasticity and is an important neurochemical basisfor learning and memory.

A number of genes that affect synaptic plasticity, compo-

nents of the synaptic vesicle or components necessaryfor synapse formation have been directly implicated in ID

(e.g. NLGN4, DLG3, SLC6A8, TM4SF2, GDI1, SYN1,IL1RAPL1, PRSS12 and GRIK2). Of these, NLGN4 andDLG3 are linked in function. Mutations in NLGN4, whichencodes neuroligin 4, occur in patients with S-XLMR and/or autism (Jamain et al., 2005). Neuroligins are mainlylocated at the postsynaptic membranes of glutamatergicsynapses and they interact with neurexins in the membranesof adjacent axons. DLG3 encodes the synapse-associatedprotein 102 (SAP102), a member of the postsynaptic mem-brane-associated guanylate kinases, which link neuroligins

to NMDA-type glutamatergic receptors. It is the firstXLMR gene to be linked directly to N -methyl-D-aspartate(NMDA) receptor-mediated synaptic activity and synapticplasticity. Protein-truncating mutations in DLG3 give rise tomoderate to severe NS-XLMR, most likely by impairing theinteraction of SAP102 withNMDA receptors and/or down-stream proteins in NMDA-receptor signalling pathways(Tarpey et al., 2004). Another example in this group isTM4SF2, encoding a highly specific cell-surface protein that

is a memberof thetetraspanin protein family. These proteinslocate to molecular complexes that include beta-1 integrinswhich are known to be involved in the regulation of actincytoskeleton organization. Thus, TM4SF2 mutations might

impair the ability of the actin cytoskeleton to drive neuriteoutgrowth, leading to aberrant neuronal morphogenesis,dentritogenesis and synaptic connectivity. Similarly, thePRSS12 protein (neurotrypsin or motopsin), a trypsin-likeserine protease expressed in the central nervous system,may also have functions that include axon outgrowth,

perineuronal environment organization and maintainingneuronal plasticity.

Genes that are linked to RNA binding, RNAsplicing, protein translation or degradation

This group of genes causes ID through the disruption of fundamental processes and includes FMR1, FTSJ1, MID1

and UBE3A. Two examples discussed in more detail here areFMR1 and UBE3A. FMR1 is associated with fragile X syn-drome, the commonest form of XLMR, with a prevalenceof approximately 1 in 5000 males and causing ID in about 1in 8000 females (Kooy et al., 2000). When patient’s chro-mosomes are cultured under special growth conditions,a fragile site at Xq27.3 tends to break. This fragile site isdue to a trinucleotide repeat (CGG) expansion in the 5’

noncoding region of FMR1. FMR1 encodes a RNA-bindingprotein (FMRP) involved in RNA transport and/or

translational regulation. FMRP binds to specific mRNAsthat are involved in dendrite development or synapse

function – the N -terminus is critical for neuronal function(Reeve et al., 2008). In the cytoplasm of neurons, it is part of large messenger ribonucleoprotein particles that containpolyribosomes. There is some evidence that FMRP medi-ates translational silencing through interaction with micro-RNAs and the RNA-induced silencing complex. However,

the binding specificity between FMRP and its partners, in-cluding interacting proteins and mRNA targets, is essen-

tially unknown. See also: The Fragile X SyndromeThe second example in this group is UBE3A, mutations

of which cause Angelman syndrome (AS). Interestingly,AS and Prader–Willi syndrome (PWS) are clinically dis-tinct disorders and yet they both arise from abnormalitiesof a small region of 15q11–q13. The syndromes have char-acteristic and distinct neurobehavioural profiles. In AS, theID is severe and there is ataxia, seizures, abnormal readingon electroencephalogram, microcephaly, facial dysmorph-ism, hyperactivityand paroxysmal laughter. By contrast, in

PWS the MR may be only mild, there is a characteristicfacial appearance and a specific behavioural abnormality,overeating (hyperphagia) resulting in severe obesity.Despite the phenotypic differences, the regions affected inthe majority of patients with these disorders overlap andthe basic defect is the same: a failure of parent-of-origin-specific gene expression. If both copies of chromosome 15derive from the mother or if there is a deletion derived fromthe father, then the individual will have PWS; if both derivefrom the father or if a deletion comes from the maternallyinherited chromosome, then the phenotype is AS. ASresults from the lack of function of the maternal copy of UBE3A, the protein product of which is involved in the

ubiquitin-mediated protein degradation pathway (Kishinoet al., 1997; Matsuura et al., 1997). By contrast, no singlegene has been implicated in PWS (Webb et al., 2008).

Genome Imbalance in IntellectualDisability

The term genome imbalance refers to any loss or gain of DNA sequences compared with the reference DNAsequence of the genome of interest. When entire chromo-somes are involved, the term aneuploidy or aneusomy is

used and when chromosomal segments are involved, theterm segmental aneusomy is used. More recently, the use of the term ‘CNVs’ has become popular, referring collectivelyto small, submicroscopic segmental aneusomies that con-tribute to genetic variation between individuals. Althoughsome CNVs exist with no apparent effect, others can in-fluence gene expression, phenotypic variation and adapta-tion by disrupting genes and altering gene dosage. Thosecausing a clinical condition are termed pathogenic CNVs.

In the following sections, well-recognized ID conditionscaused by aneuploidy and segmental aneuploidy are dis-cussed as well as examples of newly identified recurrent

syndromes (‘genomic disorders’) resulting from submicro-scopic pathogenic CNVs.



http://dx.doi.org/10.1002/9780470015902.a0005533

http://dx.doi.org/10.1002/9780470015902.a0005533



Aneuploidy

Down, Patau and Edwards syndromes are the only auto-somal trisomies that are compatible with life. They arecaused by a complete additional copy of chromosomes 21,13 and 18, respectively. Down syndrome is the most com-

mon genetic cause of ID and individuals often have specificmajor congenital malformations (e.g. of the heart and thegastrointestinal tract). Both Patau and Edwards syn-dromes are characterized by severe ID, intrauterine growthrestriction, microcephaly, congenital heart defects and sev-eral other anomalies of variable degree.

When whole chromosomes are involved, it is a challengeto identify individual genes that are dosage sensitive andthat might be responsible for the ID aspect of these con-ditions. However, comparison between individuals with

only segmental aneusomies has allowed attempts to definecritical regions. For example, in Down syndrome a criticalregion (DSCR) at 21q22 has been associated with ID and

most of the facial features. One gene within this region isRCAN1 (DSCR1, adapt78 or MCIP1). RCAN1 physicallyand functionally associates with calcineurin (a phosphatasecritical for learning and memory) by regulating the phos-phorylation/dephosphorylation of transcription factors.It is overexpressed in Down syndrome. FurthermoreCREBBP (see earlier) may also have a regulatory role in

Down syndrome through the proteasomal degradation of RCAN1. For Patau and Edwards syndromes, there hasbeen less progress. It is known that genes of the trisomicchromosomes tend to be upregulated and lead to down-stream transcriptional changes (involving genes on otherchromosomes), butno causative candidategenes forthe IDhave been identified (Nan et al., 2007).

Other numerical abnormalities discovered include sexchromosome abnormalities – Turner syndrome (45,X),Klinefelter syndrome (47,XXY), Triple X syndrome

(47,XXX) and Tetrasomy X syndrome (48,XXXX). Noneis generally associated with ID, although Turner syndromearising from structural abnormalities of the X-chromo-some can have an effect (Messina et al., 2007), the IQs of those with Triple X syndrome may be lower than siblings’and those with tetrasomy X may have mild disability inspeech development and articulation, language expressionand understanding, and reading skills.

Segmental aneusomy syndromes

Well-recognized syndromes

There are many well-recognized segmental aneusomy syn-dromes (SAS) that have ID as a characteristic of the phe-notype and most of these are described in OMIM.Rubinstein–Taybi, Angelman, Smith–Magenis, 22q11.2deletion and 9q subtelomeric deletion syndromes, are allexamples of SASs for which single gene mutations havebeen shown to be causative. For other SASs, no single genehas been found to explain the spectrum of phenotypes,

but, there has been some progress towards identifyinggenes that might contribute to the ID. One example is

Miller–Dieker Lissencephaly syndrome, due to deletionsof 17p13.3, a region that includes the gene LIS1. LIS1 isthought to regulate a dynein/dynactin complex on the endof microtubules. LIS1 mutations impair the mitotic pro-gression of neuronal progenitor cells and result in defectivemigration of surviving neurons, leading to the lis-

sencephaly (‘smooth brain’) phenotype associated with se-vere ID and epilepsy/seizures. Another example,

Williams–Beuren syndrome (WBS), is caused by a micro-deletion of about25 genes at 7q11.23; individuals have mildMR, a characteristic dysmorphic face, short stature andheart abnormalities. Here, the elastin gene (ELN ) is knownto be responsible for theheartabnormality and recently theTRIM50 gene has been found to encode an E3 ubiquitinligase suggesting that it may play a role in the ID throughdisruption of ubiquitin-mediated protein degradation inthe brain. A final example is Cri du Chat syndrome, whichresults from deletions of chromosome 5p15.2. Two genes,

Semaphorin F (SEMAF ) and d-catenin (CTNND2), mapto the critical region and may be linked with cerebraldevelopment.

For most other SASs , including Wolff–Hirshhorn andthe majority of submicroscopic interstitial and sub-telomeric SASs, the gene/s causing the ID and the otheraspects for the phenotype have yet to be elucidated.

Newly recognized syndromes/genomic disorders

The finding that submicroscopic subtelomeric SASs are acommon cause of ID led to the development of a newtechnological approach, array comparative genomic hy-

bridization (aCGH), that can identify submicroscopicCNVs at the genome-wide level, not just at telomeres(Knight and Regan, 2006). Using aCGH, it is emergingthat pathogenic CNVs account for a major proportion of previously undiagnosed individuals with ID, providingapproximately 10–17% additional molecular diagnoses inthis group. Over 100 pathogenic CNVs have been reportedand the vast majority have not reported as recurrent.

However, in some cases, the local genome architecture (thestructural organization along with DNA content) predis-poses to recurrent losses or gains in material, allowing anumber of previously unrecognized recurrent genomic dis-orders to be identified. In some cases, these are reciprocal

events to those causing known SASs. For example,Potocki–Lupski syndrome is caused by the duplicationof the 17p11.2 region deleted in SMS and 7q11.23 dupli-cation syndrome is caused by duplication of the regiondeleted in WBS. In others, namely the 17q21.31 microde-letion and microduplication syndromes, both events arerelatively newly recognized (Sharp et al., 2006; Koolenet al., 2006; Shaw-Smith et al., 2006; Kirchhoff et al., 2007).Interestingly, these examples and a proportion of AS casesseem to arise because the transmitting parent carries aninversion of the region. The inversions alter the orienta-tion of highly homologous flanking low copy repeat

(LCR) sequences (or segmental duplications) predispos-ing the intervening region to a nonallelic homologous





recombination (NAHR)-mediated deletion or duplicationin subsequent generations. Other recurrent genomic dis-orders for which NAHR of LCRs is the implicated mech-anism include the 15q24, 16p11.2-p12.2 and 15q13.3microdeletion syndromes and 16p13.11 and 1q21.1 micro-deletions that are significantly associated with ID (Sharp

et al., 2007; Ballif et al., 2007; Sharp et al., 2008; Hanneset al ., 2008; Mefford et al ., 2008). To date, little is known

about the phenotypic contribution of the genes that map tothese recurrent genomic disorder regions. For the 17q21.31microdeletion syndrome, MAPT has previously been im-plicated in autosomal dominant frontotemporal dementiaand parkinsonism and in other neurodegenerative diseases(e.g. Alzheimer disease) and haploinsufficiency for theMAPT protein might influence the maturation and out-growth of neurons, functionally explaining the severehypotonia and the moderate ID in microdeletion patients.For the 16p13.11 microdeletion syndrome, NTAN1

(asparagine-specific N -terminal amidase) is a plausiblecandidate gene – mouse models deficient for this enzymeshow altered activity, social behaviour and memory (Kwonet al., 2000). For the 15q13.3 microdeletion syndrome, a1.5 Mb critical region contains six genes includingCHRNA7 . CHRNA7 encodes a synaptic ion channel pro-tein that mediates neuronal signal transmission; its loss isconsidered the cause of the observed epilepsy/seizures. Thecause of the ID is not certain.

Polygenic Studies of IntellectualDisability

It is thought that a single, but large, set of genes locatedthroughout the genome affects most cognitive abilities anddisabilities (Plomin and deFries, 1998). Some of these genesare likely to be those identified previously and discussedabove as causative of ID or located in candidate regions.

However, in order to pinpoint additional contributinggenes, a new approach involving ‘genome-wide associa-tion’ studies is being used. These studies involve testingvery large sample numbers across thousands (or millions)of arrayed DNA markers looking for small effects thatsegregate with cognitive ability (Butcher et al., 2006). Oneexample of a neurodevelopmental condition being inves-tigated in this way is autism. Autism has a 490% heri-tability, but genome-wide association studies still representa challenge; difficulties lie in consistency of clinical classi-

fication and in replicating the results within and betweendifferent research groups (Sykes and Lamb, 2007). Inaddition, higher density arrays bring higher risks of falsepositive results and significantly more samples must betested to identify small, meaningful effects. Examples of genes for which both positive and negative results havebeen reported in autism include SLC25A12 (2q31.1),RELN (7q22) and SLC6A4 (17q11.2). However, unequiv-ocal evidence implicates a gene called Contactin associated

protein-like 2 (CNTNAP2) at 7q35 (Alarcon et al., 2008;Arking et al., 2008; Bakkaloglu et al., 2008), a member of the neurexin superfamily, mediating cell–cell interactionsin the nervous system.

A more fruitful approach than association studies seemsto have been the aCGH-based identification of a numberof

pathogenic and/or predisposing CNVs in autism samples(Christian et al., 2008). Examples include microdeletions of

neurexin 1 (NRXN1 – located at 2p16.3 and important forglutamatergic synaptogenesis), microduplicatons of 15q11-q13 (the AS and PWS region) and microdeletionsand microduplications of 16p11.2 (Kumar et al., 2008;Weiss et al., 2008). Most recently, the Contactin 4 gene,CNTN4 at 3p26.3, has been implicated (Roohi et al., 2008).CNTN4 is an axon-associated cell adhesion moleculethought to be important for the formation, maintenanceand plasticity of functional neuronal networks.

ConclusionResearch into the genetic basis of ID has gradually gainedmomentum over the past decade and now continues toadvance at an unprecedented rate. Technological advanceshave already allowed thescrutinyof thegenome farbeyondthe resolution of standard microscope-based karyotypingapproaches and the future is set to reach even greaterheights as the ability to routinely sequence and analyseentire patient genomes edges even closer. From the exam-

ples presented here, it is evident that the identification of causative genes is already shedding light on their functionaleffect on both intellectualability anddisabilityand that thisknowledge is set to increase as further contributing genesare identified. Clinically, the advances mean that moremolecular diagnosescan be provided to families affected byID. This is critical to the wellbeing of the families, helpingthem to answer the all-important question ‘why?’, givingthem more accurate prognostic information, helping themto receive appropriate clinical care and education for

affected individuals and, where appropriate, helping toclarify genetic risk for the immediate and wider familythrough improved genetic counselling. Finally, under-standing how genetically driven brain processes work to-gether to produce the spectrum of cognitive abilities and

disabilities may be the key to devising new therapeuticapproaches for the future.

Acknowledgements

This work was supported in part by the Oxford PartnershipComprehensive Biomedical Research Centre with fundingfrom the Department of Health’s NIHR BiomedicalResearch Centres funding scheme. The views expressedin this publication are those of the author and notnecessarily those of the Department of Health. I am grate-ful to Dr Niki Meston forvaluable commentsand discussion.





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