chapter 6 cell adhesion molecules in synaptopathies

Chapter 6

Cell Adhesion Molecules in Synaptopathies

Thomas Bourgeron

Abstract Synaptopathies are human disorders caused by a defect in synapse

formation or function. In the first 3 years of life, the ability of children for

learning is impressive and correlates with an intense phase of synaptogenesis in

their brains. During this critical period, cell adhesion molecules (CAMs) are

crucial factors for the identification of the appropriate partner cell and the

formation of a functional synapse. Consistent with their key roles in brain

development, mutations in brain CAMs can lead to a variety of neurological

disorders such as deafness, epilepsy, mental retardation, and autism spectrum

conditions (ASC). Furthermore, polymorphisms of brain CAMs within the

human population may also play a role in the susceptibility to milder cognitive

disorders. This chapter reports several examples of CAM mutations that are

associated with human brain disorders and highlights the emerging key roles of

these molecules in the susceptibility to neurologic and psychiatric conditions.

Keywords Autism � Psychiatry � Synapse � Synaptogenesis

6.1 Introduction

The wiring of the brain is the result of a mixture of information coming from

genetic, epigenetic, and environmental factors. The actual contribution of these

factors in the susceptibility to psychiatric conditions remains a matter of con-

siderable debate. Recently, an emerging category of disorders caused by a defect

in synapse formation or function, the so-called synaptopathies, focuses atten-

tion on several synaptic genes that cause neurological/psychiatric disorders.

Among the syndromes influenced by CAMs, autism affects about 0.7% of

children and is characterized by deficits in social communication, absence or

T. Bourgeron (*)Human Genetics and Cognitive Functions Units, Institut Pasteur, 25 rue du DocteurRoux 75724 Paris Cedex 15, Paris, Francee-mail: [email protected]

M. Hortsch, H. Umemori (eds.), The Sticky Synapse,DOI 10.1007/978-0-387-92708-4_6, � Springer ScienceþBusiness Media, LLC 2009

141

delay in language, and stereotyped and repetitive behaviors (Freitag 2007).Beyond this unifying definition lies an extreme degree of clinical heterogeneity,ranging from debilitating impairments to mild personality traits. Hence autismis not a single entity, but rather a complex phenotype encompassing eithermultiple ‘‘autistic disorders’’ or a continuum of autistic-like traits and beha-viors. To take into account this heterogeneity, the term autism spectrum con-dition/disorder (ASC/ASD) is now used.

ASC is usually diagnosed before 3 years of age, a period characterized byintense synaptogenesis in the human brain (Huttenlocher andDabholkar 1997).In that perspective, CAMs represent excellent candidates for acting as suscept-ibility factors for this syndrome. Indeed, brain CAMs are crucial factors forsynaptic contact initiation, recruitment of presynaptic and postsynaptic pro-teins, synapse maturation/stabilization or elimination, and synaptic plasticity(Dalva et al. 2007). Besides their importance in synaptogenesis, two lines ofevidence make CAMs compelling candidates for modulating inter-individualsusceptibility to psychiatric conditions.

First, their functions may be significant, but is often not vital for the organ-ism. In contrast to genes involved in the early stage of the human brain devel-opment, some CAMs may only play a role in the specificity of the wiring(Mattson and van Praag 2008). Thus, a slight atypical wiring by mutations inCAMs may cause very specific cognitive disorders and/or susceptibility topersonality dimensions without causing a severe neurological condition. Con-sistent with this hypothesis, several mutant mice for CAMs do not alwaysdisplay obvious phenotypes (Tabuchi et al. 2007, Jamain et al. 2008b).

Second, CAM-encoding genes represent a significant portion of the humangenome (Li et al. 2008) and each gene usually has several paralogous genesforming an extended gene family (Figs. 6.1 and 6.2). Therefore, due to mole-cular redundancy, a mutation in a single gene could lead to very subtle orspecific cognitive alterations rather than to a severe neurological disorder.Furthermore, several CAM possess a large combinatory of alternative promo-ters and splicing exons. This ability to create more than 100 different proteinsfrom a single gene makes CAMs among the best candidates for encodingneuronal identity (Shapiro et al. 2007). Along this line, it is very likely that ananomaly in neuronal identity may increase the susceptibility to a psychiatriccondition. In this chapter, I will present several case reports that illustrate thediversity of CAM mutations in humans and discuss how dysfunction of theseadhesive systems may contribute to these disorders.

6.2 Neuroligins and Neurexins

Neuroligins and neurexins are postsynaptic and presynaptic proteins involvedin synapse formation and maintenance (Craig and Kang 2007, see also Chapter17). Mutations affecting these proteins, as well as SHANK3, a scaffoldingprotein of the postsynaptic density (PSD) that binds to neurologins, are

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associated with ASC (Jamain et al. 2003, Durand et al. 2007). There are five

neuroligin genes NLGN1, NLGN2, NLGN3, NLGN4X, and NLGN4Y in the

human genome, but only the X-linked genesNLGN3 andNLGN4X are strongly

associated with human disorders. The first report concerned a frame-shift

mutation in the NLGN4X gene that was identified in two brothers, one with

autism and the other with Asperger syndrome (a milder form of autism without

language alteration) (Jamain et al. 2003). In the same study, a non-synonymous

mutation (R451C) of the X-linked NLGN3 gene, which affects a highly con-

served amino acid in the esterase domain, was identified in a second family with

two brothers, one with autism and the other with Asperger syndrome. These

mutations were studied at the functional level and were found to alter the

property of their neuroligin protein products to trigger synapse formation in

cultured neuronal cells (Chih et al. 2004, Comoletti et al. 2004).Several laboratories replicated the original finding and have identified inde-

pendent NLGN point mutations (Laumonnier et al. 2004, Yan et al. 2004) or

deletions (Chocholska et al. 2006, Macarov et al. 2007, Kent et al. 2008,

Lawson-Yuen et al. 2008). Among these variations, one concerns the Y-linked

geneNLGN4Y, an interesting member of the neuroligin family that is specific to

primates and is only present in males (Yan et al. 2008a). In addition, a de novo

mutation in the promoter of NLGN4X was shown to increase the transcript

level ofNLGN4X in one boy with ASC (Daoud et al. 2008). Finally, in a recent

study focused on X-linked ichthyosis (XLI) (steroid sulfatase [STS] deficiency),

Fig. 6.1 Structure of CAMs associated with synaptopathies in humans

6 Cell Adhesion Molecules in Synaptopathies 143

five affected boys from three unrelated families had an unusually large deletion

that encompass STS, the causative gene for XLI, and the NLGN4X gene (Kent

et al. 2008). Remarkably, all these patients fulfilled criteria for an autism or a

related language/communication difficulty. In contrast, none of the boys with a

deletion or presumed point mutations of STS only demonstrated autistic diffi-

culties. Besides mutations in the coding sequence, abnormal NLGN3 and

NLGN4X spliced isoforms were detected in blood cells from individuals with

ASC (Talebizadeh et al. 2006). If these abnormal transcripts are actually pre-

sent in the brain of the affected individuals, this finding may represent a new

type of NLGN alteration in ASC patients.Although independent mutations in NLGN3 and NLGN4X were identified

and functionally validated as susceptibility factors for ASC, these mutations

may only concern a limited number of cases (<1% of the individuals) (Vincent

et al. 2004, Gauthier et al. 2005, Ylisaukko-oja et al. 2005, Blasi et al. 2006). In

addition, the specificity of the disorder associated withNLGN4Xmutations can

Fig. 6.2 Phylogeny of the human CAMs with their respective associated disorders. The questionmarks indicate genes proposed as susceptibility genes for autism, but with no formal proof forassociation. The phylogeny trees were obtained using human protein sequences and theneighbor-joining method implemented in the CLUTALW2 program (http://www.ebi.ac.uk/Tools/clustalw2/index.html)

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greatly differ from one individual to another, even when they belong to the samefamily and carry the same mutation. Indeed, mutations within NLGN4X wereassociated with mental retardation (Laumonnier et al. 2004), typical autism(Jamain et al. 2003, Yan et al. 2004), Asperger syndrome (Jamain et al. 2003),and more recently with Gilles de la Tourette syndrome (Macarov et al. 2007,Lawson-Yuen et al. 2008), a neurological disorder that is characterized bymotor and vocal tics and behavioral anomalies. To date, only a single case ofan NLGN4X deletion in a male with normal intelligence and apparently noautistic features has been reported (Macarov et al. 2007).

Following these initial findings, Nlgn3 R451C knockin and Nlgn4 knockoutmice were generated. Both mutant mice display reduced social interactionswhen compared with wild-type mice (Tabuchi et al. 2007, Jamain et al.2008a). The Nlgn3 R451C knockin mice also show increased GABAergicsynapses and inhibitory postsynaptic currents (IPSC). Interestingly, Nlgn4KO mice exhibit reduced ultrasonic vocalizations (USV). This seems to be theconsequence of a reduced motivation to ‘‘communicate’’ rather than a problemin the vocalization process per se. Thus, together with mutant mice for Fmr1(fragile X syndrome) and Mecp2 (Rett syndrome), the neuroligin mutant micerepresent the first animal models for ASC based on results obtained directlyfrom human genetics studies.

A third gene in the neuroligin pathway, SHANK3, is associated with ASC,but does not code for a CAM. SHANK3 is a scaffolding protein of the post-synaptic density (PSD), which binds to NLGN, and is known to regulate thestructural organization of dendritic spines (Boeckers et al. 2002, Meyer et al.2004). The SHANK3 gene is located on chromosome 22q13, a region deleted inseveral individuals with ASC (Manning et al. 2004, Durand and Bourgeron2008).Mutations in or a loss of one copy of SHANK3 are associatedwith autism,whereas the presence of an extra copy appears to be associated with Aspergersyndrome or attention-deficit hyperactivity disorder (ADHD) (Durand et al.2007, Moessner et al. 2007). Among the variations identified, a de novo frame-shift mutation that originated in a mother with germinal mosaicism has beenfound in two brothers with autism. Expression experiments of the rat Shank3cDNA carrying the frame-shift mutation in cultured neurons indicate that thetruncated protein, in contrast to the full-length protein, is absent from thedendritic spines. Recently, several independent mutations and deletions ofSHANK3 were identified in individuals with ASC (Moessner et al. 2007, Sebatet al. 2007, Gauthier et al. 2008), providing further evidences that the synapticpathway, which includes NLGN and SHANK3, is associated with ASC.

Finally, the fourth ASC susceptibility protein which was identified within theneuroligin pathway is NRXN1, the presynaptic binding partner of NLGNs.NRXN1 is located on chromosome 2p16 and codes for the long neurexin a andthe short neurexin b form (Fig. 6.1). Furthermore, NRXN transcripts areextensively differentially spliced, leading in theory to more than 100 differentisoforms (Tabuchi and Sudhof 2002). In humans, the first NRXN1 alterationwas identified in a 7-year-old boy with an IQ of 74 and a complex psychiatric


phenotype including attention-deficit disorder and Asperger syndrome (Fried-man et al. 2006, Zahir et al. 2008). The patient carried a de novo 320 kb deletionof NRXN1 that removes the promoter and first exon of NRXN1a, but appar-ently does not affect NRXN1b. The patient also had dismorphic features, suchas frontal bossing, anomalies in the anterior and posterior hairlines, and dorsalscoliosis with 13 ribs on left, bifid right second rib, hemivertebrae and fusions ofT2, T3, T4, and fusion of L4 and L5. The secondNRXN1 genetic alteration wasdetected using a whole genome approach performed by the Autism GenomeProject Consortium that investigated 1168multiplex families for the presence ofsmall genomic alterations called copy number variants (CNV) (Szatmari et al.2007). This analysis detected a de novo deletion in the NRXN1 gene, removingseveral exons from both the NRXN1a and NRXN1b, in two sisters with typicalASC. More recently, two cases with ASC harboring translocations within ornear NRXN1 were identified (Kim et al. 2008). The first one is a female withASC and carrying a paternally inherited translocation that directly disruptsNRXN1a within intron 5. The second case is a male patient carrying a de novotranslocation with a breakpoint at �750 kb of the NRXN1 gene.

Following these reports, a mutation screening of the NRXN1 codingsequence was performed in two cohorts of ASD subjects (Kim et al. 2008,Yan et al. 2008b). A number of rare variants altering evolutionary conservedresidues were identified. However, as for some translocations, these pointmutations were inherited from healthy parents, indicating that other factorsare also involved in producing ASC. In addition, likeNLGN4X, the phenotypesassociated with NRXN1 mutations are not specific to ASC. Indeed, one dele-tion, which partially overlaps with the first deletion described in an ASCpatient, was identified in two siblings with schizophrenia and in their asympto-matic mother (Kirov et al. 2008).

Only limited data are available for understanding the role of theNRXN–NLGN–SHANK pathway at synapses in the human brain, but studiesusing neuronal cell culture and animal models have provided crucial informa-tion. First, NLGNs andNRXNs enhance synapse formation in vitro (Scheiffeleet al. 2000), but are not required for the generation of synapses in vivo(Varoqueaux et al. 2006). Indeed, results from knockout mice demonstratethat neither NLGNs nor NRXNs are required for the initial formation ofsynapses, but both are essential for synaptic function and the survival of themouse. Therefore, NLGNs may not establish synapses, but may specify andvalidate them via an activity-dependent mechanism, with different neuroliginsacting on distinct types of synapses. This model, proposed by Chubykin et al.(2007), reconciles the overexpression and KO phenotypes and suggests thatNLGNs contribute to the activity-dependent formation of neural circuits(Chubykin et al. 2007) (see Chapter 17).

Second, NLGNs and NRXNs are also emerging as central organizing mole-cules for excitatory glutamatergic and inhibitory GABAergic synapses in themammalian brain (Graf et al. 2004, Prange et al. 2004). NLGN1 and NLGN3are specific to glutamatergic synapses, whereas NLGN2 is restricted to

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GABAergic synapses. Whether NLGN4 andNLGN4Y are localized to specificsynapses remains unknown. The selectivity for glutamatergic vs. GABAergicsynapses is also conferred by alternative splicing of NRXN/NLGN (Chih et al.2006, Comoletti et al. 2006). Consistent with this role in the establishment of aspecific synapse, the mutant mice carrying the R451C Nlgn3 mutation show anincreased number of GABAergic synapses and inhibitory currents, suggestingthat the R451C mutation is a gain-of-function mutation (Tabuchi et al. 2007).Although NLGN2 mutations were not reported in ASC, mutant mice withenhanced expression of Nlgn2 display enlarged synaptic contact size and vesiclereserve pool in frontal cortex synapses and an overall reduction in the excitation/inhibition ratio (Hines et al. 2008). These animals also manifest a stereotypicjumping behavior, anxiety, impaired social interactions, and enhanced incidenceof spike-wave discharges. This role of NRXN/NLGN for synaptic specificity ishighly relevant to ASC since an imbalance between excitation and inhibition canlead to epilepsy, a disease observed in almost 25% of individuals with ASC.

Third, the scaffold formed by SHANK3 proteins at the postsynaptic density(PSD), which binds to the NLGN, is known to regulate the structural organiza-tion of dendritic spines (Roussignol et al. 2005). Shank proteins are a family ofthree members composed of Shank1, Shank2, and Shank3, which are crucialcomponents of the postsynaptic density. Shank proteins link ionotropic andmetabotropic glutamate receptor complexes to the cytoskeleton. Shank pro-teins and their binding partners are involved, in vitro, in regulating the size andshape of dendritic spines (Roussignol et al. 2005). Remarkably, mice carrying anull mutation of Shank1 exhibit smaller dendritic spines, weaker synaptictransmission, increased anxiety-related behavior, and impaired contextualfear memory, but show enhanced spatial learning (Hung et al. 2008).

Taken together, these results strongly suggest that synapse specificity andmaintenance have an important role in the susceptibility to ASC (Fig. 6.2).However, the complex genotype–phenotype relationships indicate that otherfactors modulate the expression and the severity of the syndrome. Among othersynaptic genes that could play such a modifier role, CAMs belonging to thecontactin (CNTN) and the contactin-associated protein (CNTNAP) familiesrepresent very promising candidates.

6.3 Contactin and Contactin-Associated Proteins

The human contactin family is a part of the immunoglobulin superfamily andconsists of six members: CNTN1 (contactin or F3), CNTN2 (TAG-1), CNTN3(BIG-1), CNTN4 (BIG-2), CNTN5 (NB-2), and CNTN6 (NB-3). CNTNs arecharacterized by six Ig-like and four fibronectin type III (FN III)-like domainsfollowed by a glycosylphosphatidyl inositol (GPI) moiety at the COOH term-inal (Fig. 6.1). In mice, contactins act in different processes, such as axonal anddendritic interactions as well as in the organization of the nodes of Ranvier.


CNTN1 and CNTN2 are essential for the molecular organization of paranodesand juxtaparanodes of myelinated fibers, respectively (Boyle et al. 2001, Traka etal. 2003). Mice deficient for CNTN1 display a severe ataxic phenotype, which isconsistent with defects in the cerebellum and survive only until postnatal day 18(Boyle et al. 2001). CNTN2 is required for proper neuronal migration of theprecerebellar nuclei (Denaxa et al. 2005). CNTN4-deficient mice are less affectedand display aberrant projection of axons from olfactory sensory neurons tomultiple glomeruli (Kaneko-Goto et al. 2008), whereas CNTN5-deficient miceshow aberrant responses to acoustic stimuli (Li et al. 2003). Finally, CNTN6deficiency leads to impaired motor coordination (Takeda et al. 2003).

In humans, so far only alterations of CNTN3 and CNTN4 have beenreported. CNTN4 is located in the region for 3p deletion syndrome, a rarecontiguous-gene disorder characterized by developmental delay, growth retar-dation, and dysmorphic features. In 2004, Fernandez et al. identified a childwith the characteristic physical features of 3p deletion syndrome, who carried ade novo balanced translocation that disrupts CNTN4 (Fernandez et al. 2004).Interestingly, this patient, who exhibited both verbal and nonverbal develop-mental delays, was reevaluated in 2008 and was found to fulfill all criteria forASC (Fernandez et al. 2008). Two additional families were reported (Roohiet al. 2008). One family included three affected siblings with ASC: two of themhad a paternally inherited CNTN4 deletion, but one affected brother did nothave the deletion. In the second family, the affected boy carried a paternallyinherited duplication. Finally, a homozygous deletion of approximately 500 kbfrom the CNTN3 gene was recently identified in one child with ASC born fromconsanguineous parents (Morrow et al. 2008).

Although genetic data point at CNTN3/CNTN4 as a susceptibility gene forASC, the lack of straight segregation between the genetic alterations and thedisorder indicates that a single CNTNmutation is not enough to produce ASC.The strongest support for a role of the CNTN pathway in the susceptibility toASC came from the study of CNTNAP2 (Caspr2), a binding partner of CNTNthat possesses strong homology to NRXN (Fig. 6.1) and is associated with ASCin independent samples of patients (Strauss et al. 2006, Bakkaloglu et al. 2008,Alarcon et al. 2008, Arking et al. 2008).

CNTNAP2 mutations were originally identified in Amish individuals, whowere diagnosed with recessive cortical dysplasia-focal epilepsy syndrome(CDFE) and language regression (Strauss et al. 2006). Notably, two-thirds ofthe affected individuals also met criteria for ASC. Especially when the carboxy-terminal of the CTNAP2 protein is truncated, CTNAP2 mutations areassociated with severe autism with medication-insensitive temporal lobe sei-zures, language regression, and low IQ. Following this initial report, severalindependent studies showed that chromosomal alterations and rare single basepair mutations, as well as common variation in CNTNAP2, can contribute toASC risk. First, Bakkaloglu et al. reported a de novo 7q35 inversion thatdisrupts CNTNAP2 in a child with autistic features (Bakkaloglu et al. 2008).This finding led them to sequence all 24 exons of the gene in 635 affected and

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942 control individuals. Thirteen rare variants were identified in affected casesand of these eight were predicted to be deleterious. Although these variants werealso found in the control cohort, they were roughly twice more frequent inaffected than in control individuals. One variant (I869T) was found to bepresent in four affected individuals from three different families, but was notpresent in >4000 chromosomes from unaffected individuals.

Alarcon et al. genotyped 172 parent–child trios at 2758 single nucleotidepolymorphisms (SNPs) across a 10 cM linkage peak at 7q35 (Alarcon et al.2008). Only SNP rs2710102, which is located in CNTNAP2, showed a signifi-cant association with ASC, but only in male probands. This association wasspecifically related to the delay in the ‘‘age of first word’’. In a child with ASCthe authors also reported a paternally inherited microdeletion within an intronofCNTNAP2 that was not seen in 1000 control chromosomes. Finally, anothercommon SNP variant (rs7794745) within theCNTNAP2 gene was identified byassociation mapping with strictly defined autism cases. It was also confirmed inan independent replication population (with broader diagnostic inclusioncriteria) (Arking et al. 2008).

Similar to NLGN4X and NRXN1, CNTNAP2 alterations are not specificto ASC, but are also associated with other disorders such as epilepsy andschizophrenia (Friedman et al. 2008) and Gilles de la Tourette syndrome(Verkerk et al. 2003). Moreover, a translocation disrupting CNTNAP2 wasreported for several members of a family withmultiple congenital malformations(scoliosis, single kidney, hearing loss, ptosis, and vision loss because of cataractand affected optic nerve), severe mental retardation, and an absence of languagedevelopment (Belloso et al. 2007). Remarkably, in the same family, severalindividuals carrying the CNTNAP2 translocation were phenotypically normal.

The association between the CNTN/CNTNAP pathway and ASC is espe-cially interesting as it provides new information on the possible mechanismsleading to ASC. CNTN4 had a neurite outgrowth-promoting activity whenused as a substrate for mouse neurons in vitro. In vivo, Cntn4 expression isregulated by neural activity and its product acts as an axon guidance moleculethat mediates proper neuronal wiring in the mouse olfactory system (Kaneko-Goto et al. 2008). It is also highly expressed in the cerebellum and in the CA1pyramidal cells in the hippocampus (Yoshihara et al. 1995). Thus, it is likelythat CNTN4 plays functional roles in the formation and maintenance of neuralcircuits in these regions. Cntap2 (Caspr2), at least in mice, is differentiallyexpressed in distinct neuronal structures, including the soma and dendrites,and in specific short-segmented pairs along myelinated axons. Its expression inmyelinated nerves is mostly confined to the axon at the juxtaparanodal regionand to some isolated paranodal loops. In the juxtaparanodal region, Cntnap2 isprecisely colocalized with Shaker-like potassium channels. The complete loss ofCntnap2 eliminates spatial clustering of axonal inwardly rectifying potassiumchannels, but does not result in overt cortical dysplasia or spontaneous seizures(Poliak et al. 2003). Therefore, patients carrying mutations inCNTNAP2mighthave slight to severe alterations of the attachment of the axon to the glia cell and


mislocalization of ion channels at the juxtaparanodal junction leading to analteration of neurotransmission velocity. However, in addition to their scaffold-ing roles at the nodes of Ranvier, CNTN/CNTNAP could also be involved incortical histogenesis and may mediate intercellular interactions during latterphases of neuroblast migration, laminar organization, or axonal pathfinding.Finally, the possibility cannot be excluded that some members of the CNTN/CNTNAP family directly participate in synapse formation/validation in asimilar way as the NLGN–NRXN–SHANK pathway. Interestingly, theexpression pattern of humanCNTNAP2 greatly differs from its mouse ortholog(Abrahams et al. 2007). Indeed, human CNTNAP2 is consistently expressed athigh levels in the prefrontal and anterior temporal cortex, as well as in the dorsalthalamus, caudate, putamen, and amygdala in midgestation fetal brains. Incontrast to the findings in humans, mouse Cntnap2 is broadly expressed in thedeveloping rodent brain. Therefore, it was hypothesized that humanCNTNAP2 has acquired a new specific role in circuits that are involved inhigher cortical functions, including language (Abrahams et al. 2007).

6.4 Cadherins and Protocadherins

In the human genome, the most compelling candidate genes for determining apart of neuronal identity are those belonging to the cadherin family (seeChapter 7). Cadherins (CDH) are single-pass transmembrane proteins, whichare characterized by the presence of cadherin repeat protein domains in theirextracellular segments. Each of these 110 amino acid repeats forms ab-sandwich and the presence of calcium is essential for cadherin-adhesivefunction. The human genome encodes more than 100 CDH, most of whichare expressed in the nervous system. Cadherins have been classified into severalsubfamilies, including the classical cadherins, which are linked to the actincytoskeleton through catenin, and the protocadherin family, which has acomplex genomic organization with multiple variable exons and a set of con-stant exons resembling immunoglobulin (Ig) and T-cell receptor (TCR) genes(Hirayama andYagi 2006). Several human disorders are caused bymutations inCDH/PCDH. These include Usher syndrome, EFMR (epilepsy and mentalretardation limited to females) syndrome, and most likely ASC.

Usher syndrome (USH) is the most frequent cause of combined deafblind-ness in man (Roux et al. 2006). It is a clinically and genetically heterogeneoussyndrome caused by at least eight identified USH genes. The two mostprevalent mutated genes encode CAMs: the Cadherin 23 (CDH23) and theprotocadherin 15 (PCDH15). Mutations in CDH23 are linked to the recessiveUSH1D and to the recessive non-syndromic deafness DFN12. Mutations inPCDH15 are responsible for the recessive USH1F and recessive deafnessDFNB23. Analyses of the mice bearing mutations in the pcdh15 and Cdh23gene revealed that these CAMs play important roles in membrane adhesion at

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specialized synapses of photoreceptor and inner hair cells. In the inner ear,CDH23 and PCDH15 interact to form tip-link filaments in sensory hair cells(Kazmierczak et al. 2007). In the retina, they are localized in the connectingcilium and the basal body complex, as well as the ribbon synapses of rod andcone photoreceptor cells. Most interestingly, by 5 months of age mice doubleheterozygous for Cdh23 and Pcdh15 mutations exhibit deafness and abnormalstereocilia in the outer and inner hair cells of the organ of corti. Single hetero-zygotes lack this pathology (Zheng et al. 2005). This digenic inheritance of aUSH1 phenotype was also reported in three unrelated families with affectedindividuals carrying heterozygous mutations in both CDH23 and PCDH15.

Another remarkable example of a human disorder that is caused by a CDHmutation is EFMR, an X-linked disorder, which is characterized by epilepsy andmental retardation and has a unique inheritance pattern (Dibbens et al. 2008). Ingeneral, disorders arising from mutations on the X chromosome typically affectmales and have unaffected carrier females. In contrast, EFMR spares transmittingmales and affects only carrier females. Recently, Dibbens et al. identified severalindependent protocadherin 19 (PCDH19) gene mutations in seven families. Fivemutations result in the introduction of a premature termination codon. A study oftwo of these demonstrated a nonsense codon-mediated decay ofPCDH19mRNA.Two missense mutations are predicted to affect the adhesiveness of the PCDH19protein by impairing calcium binding. PCDH19 is expressed in human and mousedeveloping brain, but its actual role remains unknown. To explain the sex-limitedmode of inheritance the authors proposed a mechanism of rescue in males by a Ychromosome gene, PCDH11Y (Durand et al. 2006). PCDH11Y originates from atranslocation of thePCDH11X gene after the divergence between chimpanzees andhumans; therefore, it is one of the few genes that are specific to the hominoidlineage and are absent from other primates.

However, an alternative hypothesis could explain the female-limited pheno-type (Fig. 6.2). First, it should be noted that PCDH19 is subjected to X inactiva-tion and therefore a single neuron most likely do not express both alleles. Thealternative hypothesis proposes that the disorder is the consequence of an ‘‘allelicincompatibility’’ between two different sets of neurons, one expressing the wild-typesequence and the other expressing the mutant sequence. Indeed, heterozygous-affected females have two sets of neurons, which either express the wild-type orthe mutated PCDH19 gene. In contrast, unaffected males carrying a PCDH19mutation only express the mutated forms of PCDH19, and control males andfemales only express the wt sequence. Therefore, the presence of two distinctpopulations of neurons on the basis of PCDH19 expression may scramble specificneuronal identity during development. If this hypothesis is correct, female homo-zygous for the mutation should not be affected and males with an X chromosomemosaicism should be affected. However, as PCDH19 mutations are very rare nosuch case has so far been described (Fig. 6.3).

Allelic incompatibility is a well-known cause of maternal–fetal incompatibilityreactions and this concept may also apply to brain development/function at theneuronal level. This hypothesis is strengthened by the finding that even autosomal


PCDH genes are monoallelically expressed in single neurons (Esumi et al. 2005).Therefore, this huge diversity of PCDH expression (Hilschmann et al. 2001) com-bined with a modulation between different allelic interactions could increase thenumber of specific individual neuronal cell identities and could play a crucial role inestablishing the blueprint for the neuronal networks in each individual human.

6.5 CAMs Polymorphisms and the Susceptibility to Psychiatric

Conditions

In the previous sections, we mainly focused on CAM mutations, which causemonogenic inheritable conditions. However, the sequence of the human gen-ome revealed that a relatively large number of genetic variations exist betweenindividuals. The most frequent and studied variations concern SNPs and

Fig. 6.3 Possible brain wiring alterations caused by CAM mutations in synaptopathies. Muta-tions in cadherins, protocadherins, or contactins could lead to abnormal brain wiring byscrambling neuronal identity and/or axonal pathfinding cues. In heterozygote individuals (m/+), the presence of two different sets of neurons could have a more drastic effect than inhomozygote individuals who harbor in both cases (+/+ or m/m) a homogenous populationof neurons. Mutations in the contactin and contactin-associated proteins could lead touncoordinated information processing by modifying neuronal transmission velocity (V) indifferent parts of the brain. Mutations in neuroligins and neurexins could lead to abnormalinformation processing by modifying the excitation/inhibition ratio and/or synapse stabiliza-tion. m, mutated allele; +, control allele

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CNVs. The Hapmap consortium explored human genome diversity and hasidentified more than 3 million SNPs that are distributed among the humanpopulation (Frazer et al. 2007). The actual number of reported CNVs (>1500) isless clear as such small structural variants are sometimes difficult to detect(Redon et al. 2006).

It is still difficult to evaluate the contribution of these polymorphisms tohuman disorders. Concerning CAMs, their different allelic forms among indi-viduals may play a key role in the susceptibility to psychiatric disorders sincethey increase the number of distinct CAM interactions during axonal pathfind-ing and synapse formation. Thus, in theory, CAM polymorphisms may causeslight differences in the wiring of each individual brain. Several CAM poly-morphisms were tested for correlating with a susceptibility to psychiatricconditions. For example, NrCAM, PCDH8, and PCDH11Y were studied inpatients with ASC and schizophrenia (Bray et al. 2002, Hutcheson et al. 2004,Bonora et al. 2005, Durand et al. 2006, Sakurai et al. 2006). However, none ofthese studies has provided clear evidence to implicate any of these genes in thesedisorders. In parallel, whole genome analyses (WGA) represent powerful meth-odologies to detect susceptibility genes for human disorders. These unbiasedapproaches sometimes detect signals within CAMs. Interestingly, two indepen-dent studies detected SNPs within the NRXN1 gene in strong association withnicotine dependence (Nussbaum et al. 2008) andwithinNRXN3 associated withsusceptibility for polysubstance addiction (Hishimoto et al. 2007). Althoughthese WGA studies need to be replicated and validated at the functional levels,they will most likely shed light on new pathways that contribute to the suscept-ibility for specific human brain disorders.

6.6 Conclusions and Perspectives

Several considerations can be made from the examples presented in this chapter.First, mutations in CAMs can obviously affect the wiring and/or the plasticity ofsynapses in the human nervous system. However, it is not clear whether thedisorder is the consequence of an abnormal wiring or due to an alteration insynaptic plasticity or to both processes. The second consideration concerns thevery complex genotype–phenotype relationship, which has been observed forCAMmutations. Indeed, the specificity and the severity of the disease conditionsthat are associated with brain CAM mutations remain very difficult to predict.An additional example of this diversity is illustrated by the mutations in the X-linked L1CAM gene that are associated with at least four different syndromes:HSAS (X-linked hydrocephalus with stenosis of the aqueduct of Sylvius),MASAsyndrome (mental retardation, aphasia (delayed speech), spastic paraplegia,adducted thumbs), SPG1 (X-linked complicated hereditary spastic paraplegiatype 1), and X-linked complicated corpus callosum agenesis. These disorders arenow collectively referred to as L1 syndrome.


This complex genotype–phenotype relationship is most likely due to severalintrinsic properties of the CAMs: (1) their huge diversity within the humangenome; (2) their close relationship with neuronal activities and plasticity; and(3) the modifying roles of CAM polymorphisms in the establishment of theneuronal networks. Therefore, the severity and the specificity of the disordersmay be the consequence of a combination of mutations in different CAMs, asillustrated by the CDH23 and PCDH15 digenic inheritance of Usher syndrome(Zheng et al. 2005).

Only a global genetic and functional analysis of all CAMs may enable us tobetter predict the consequence of CAMmutations in humans. These investigationsare warranted since mutations in brain CAMs are obviously associated with anincreasing number of human disorders. Indeed, several high-throughput sequen-cing projects are currently in progress to discover new genes that are associatedwith a susceptibility to psychiatric disorders, such as ASC, schizophrenia, orbipolar disorders. A number of synaptic CAMs, such as SynCAMs, DsCAMs,Sidekicks, have not been associated with a human disorder. However, the discov-ery of such associations is probably just a question of time.

Acknowledgments I would like to thank Michael Hortsch and Hisashi Umemori for theircritical reading of this chapter. This work was supported by the Pasteur Institute, INSERM,Assistance Publique-Hopitaux de Paris, FP6 TISM MOLGEN, FP6 ENI-NET, FondationOrange, Fondation de France, Fondation biomedicale de la Mairie de Paris, Fondation pourla Recherche Medicale and FondaMental.

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chapter 6 cell adhesion molecules in synaptopathies

Documents

human brain disorders

polymorphisms of brain

human disorders

cams compelling candidates

psychiatric conditions

functional synapse

sticky synapse

emerging category of