Major components of myelin in the mammalian CNS and PNS 19of the protein.. In Olig1-null mice, oligodendrocyte progenitors born in the brain are able to migrate, proliferate, anddifferen
Trang 1Major components of myelin in the mammalian CNS and PNS 19
of the protein Cell-type specific alternative splicingbetween neurons and myelinating cells accounts for two of the splice isoforms; neuronal isoformsinclude a mucin domain, while myelinating cellsinclude an additional FNIII domain (Southwood
et al., 2004; Tait et al., 2000) At least two promotershave been identified and may confer relative cell-typespecific expression in neurons and oligodendrocytes(unpublished)
Nfasc is a type I glycoprotein with a single membrane domain It is an IgSF member belonging
trans-to the L1 subgroup and typically contains six Igdomains and three FNIII domains in its extracellularregion Although Nfasc has been studied because
of its neurite outgrowth promoting activity and ticipation in axon–axon interactions (Volkmer et al.,1996), it has most recently been characterized withregard to its roles in myelination and node of Ranvierformation
par-In the CNS, both the neuronal and myelin forms of Nfasc are targeted to paranodal regions ofmyelin sheaths where they participate in formation
iso-of axoglial junctions along with contactin and Caspr(Sherman et al., 2005; Tait et al., 2000) Neuronal
splicing of the Nfasc gene encodes a 186 kD form of
the protein (NF186) while oligodendrocytes andSchwann cells synthesize NF155 NF186 is also targeted to nodes of Ranvier, where it may par-ticipate in macromolecular complexes to stabilizethe association of astrocyte processes with the nodalaxonal membrane In the PNS, NF155 synthesized
by Schwann cells is targeted to myelin paranodesand axons target NF186 only to nodes of Ranvier
Deletion of the Nfasc gene in mice results in the
absence of axoglial junctions at myelin paranodes,the failure of Schwann cell microvilli adhesion to the nodal axon, reduced saltatory conduction in asubpopulation of myelinated fibers, and early death(Sherman et al., 2005)
Myelin lipids
Traditionally, scholarly contributions from brainlipid research to our understanding of the molecularcomponents of the nervous system have been promin-ent, although a switch to proteinaceous componentstriggered by recombinant DNA technologies in recentdecades has shifted the focus of neurochemistry
A renaissance of lipid biochemistry in the nervoussystem is in progress and has yielded very importantinsights into function, particularly at the level of themyelin sheath (Taylor et al., 2004)
To underscore their importance, lipids comprise37% of total rat brain dry weight, but in purifiedmyelin it exceeds 70% and is more than 50% complexlipids and cholesterol Indeed, myelin is one of themost protein-poor membranes known (Norton andCammer, 1984) Recent studies show that, like pro-teins, myelin lipids do not simply form the amorphousstructures that were envisioned in the fluid mosaicmodel (Singer and Nicolson, 1972), but rather areassembled into highly organized domains that regu-late structural protein clustering, receptor signalingactivity, protein–protein and cell – cell interactions.The most intensively studied of these domains are lipidrafts, which are detergent resistant and enriched inglycolipids and cholesterol (Taylor et al., 2002).Several knockout mice have been generated toablate different classes of myelin glycolipids and thesehave focussed on inactivating key enzymes in thebiosynthetic pathways Thus, ablation of the genesencoding ceramide sulfotransferase (CST), to eliminatesulfated glycolipids, or ceramide galactosyltrans-ferase (CGT) to eliminate galactosyl and sulfated gly-colipids, cause axoglial junction phenotypes largelylimited to the CNS (Coetzee et al., 1996; Honke et al.,2002) These junctions form during myelinogenesisbut eventually dissipate and cause myelin paranodalloops to dissociate from the axon with variable loss
of compartmentalization and mixing of nodal andjuxtaparanodal ion channels Elimination of complexgangliosides by ablating GM2/GD2 synthase alsocauses myelination defects, although the phenotype
is mild and appears to be more like a late-onset gressive disorder related more to motorneuron dys-function and Wallerian degeneration than to myelinsheath abnormalities (Chiavegatto et al., 2000).Myelin glycolipids are also of importance to diseaseinvolving the immune system, particularly Guillain–Barré syndrome and other inflammatory neuropathieswhich lead to PNS myelin or neuromuscular dys-function (Hughes and Cornblath, 2005; Overell andWillison, 2005) Thus, molecular mimicry stemming
pro-from infectious illnesses (often Hemophilus influenzae and Campylobacter jejuni infections) leads to the pro-
duction of antibodies that cross-react with PNS gliosides (GD1, GD3, or GQ1b) and myelin proteinsthat may disrupt myelin paranodes (Kwa et al., 2003)
gan-Transcriptional regulation of myelin genes
Transcriptional regulation of myelin genes has been
an area of study for relatively few laboratories in themyelin field and, in general, the data are relatively
Trang 220 ALEXANDER GOW
difficult to obtain Working with primary drocyte cultures is difficult because large numbers ofcells are not easily obtained, particularly from mice,and transfection efficiencies are low A few cell lineshave been generated for myelinating cells; however,these studies yield data of variable quality and should
oligoden-be interpreted with a healthy dose of skepticism asillustrated below Accordingly, I only deal with two
transcription factors for which in vivo data are
avail-able from knockout mouse studies Importantly,these data provide genetic evidence of genes that aredownstream of the transcription factor activity; they
do not demonstrate that the transcription factorbinds to the promoters/enhancers of those down-stream genes
found to act as a repressor of the PLP1 and MBP genes
(Awatramani et al., 2000) and several consensusNkx6-2 binding sites are present in the proximal
promoter regions of these genes Using an in silico
approach, Farhadi and colleagues identified
evolu-tionarily conserved binding sites in the MBP
pro-moter/enhancer (Farhadi et al., 2003) However,
expression of these genes is unperturbed in
Nkx6-2-null mice (Cai et al., 2001; Southwood et al., 2004),
indicating that the transfection data are largely in vitro artifact Consistent with the cell culture experi-
ments, Nkx6-2 appears to act as a repressor in
oligo-dendrocytes in vivo, but this transcription factor
actually regulates at least two genes associated with
axoglial junction formation, NF155 and contactin
(Southwood et al., 2004)
Olig1 and Olig2
The transcription factors, Olig1 and Olig2, are basichelix-loop-helix proteins coordinately expressed inneural progenitor cells and oligodendrocytes duringdevelopment and in oligodendrocytes postnatally
Both proteins appear to regulate expression of thesame genes in oligodendrocytes and each can parti-ally compensate for the other However, Olig1 func-tion is far more important in brain than spinal cordand the converse is true for Olig2 (Lu et al., 2002,Xin et al., 2005)
In Olig1-null mice, oligodendrocyte progenitors
born in the brain are able to migrate, proliferate, anddifferentiate to the point of recognizing and makingcontact with axons; however, myelinogenesis isarrested at this point which is just prior to expression
of major myelin genes such as MAG, PLP1, and MBP
(Xin et al., 2005) Arnett and colleagues (Arnett et al.,2004) suggest that Olig1 is only required for remye-lination in the brain; however, this partial pheno-type likely stems from a technical problem with theknockout construct that masks the developmentalphenotype by enabling Olig2 to compensate for theabsence of Olig1 during myelinogenesis Thus, Olig1
is genetically upstream of a number of myelin-specific
genes in vivo, although it seems unlikely that these genes are direct targets of Olig1 In contrast, Olig1-
null oligodendrocytes in primary cell culture canoverride this arrest in myelinogenesis and can syn-thesize myelin membrane and at least some myelin
proteins (Xin et al., 2005) In Olig2-null mice, spinal
cord oligodendrocyte precursor cells are apparentlynever born so it is unclear if this transcription factorregulates myelin gene expression (Lu et al., 2002)
The notion of myelin as an immune-privileged compartment
Originally, the concept of immune privilege arosefrom transplantation studies because of the relativelack of immune system activation toward grafted tissue in specific locations in the body such as thebrain and the eye (reviewed by Bechmann, 2005) Inlight of the discovery that adaptive immunity, to dis-tinguish “self” from “non-self”, is established perinat-ally in at least some mammals, the immune-privilegedcompartment concept was expanded to account forthe absence of immune activation toward proteinsthat are not expressed until well after birth
From early morphological studies on Sertoli cells
in the testis and subsequently in oligodendrocytemyelin sheaths, a common perception about thefunction of tight junctions assembled in these cellswas that they defined immune-privileged compart-ments (reviewed in Abraham, 1991; Mugnaini andSchnapp, 1974) Thus, spermatocyte- and myelin-specific proteins that are not expressed in the peri-natal period during the establishment of immuneself-tolerance require lifelong sequestration from the immune system to avoid recognition as foreignantigens
This notion is consistent with the pathogenesis
of autoimmune orchiditis in the testis and multiple
Trang 3Major components of myelin in the mammalian CNS and PNS 21
sclerosis in the CNS, which were postulated to stemfrom the dysfunction of tight junctions and therelease of “protected antigens” into the interstitiumwhere they could be recognized by the immune
system However, the phenotype of claudin 11-null
mice, which includes male sterility and reducedsaltatory conduction velocity in the CNS, does notinclude signs of autoimmune disease in the testis
or CNS, either in terms of infiltrating immune cells
or the production of autoimmune antibodies (Gow
et al., 1999) Accordingly, this mutant casts doubt
on the longstanding notion that myelin proteins areshielded from the immune system by myelin tightjunctions to protect against the induction of multiplesclerosis
Acknowledgments
This work was supported by grants from NINDS, NIH (NS43783) and the National Multiple SclerosisSociety (RG2891)
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Trang 8The condition recognized today as multiple sclerosis(MS) was first described in the early nineteenth century (Cruveilhier, 1829 – 42; Carswell, 1838;
Frerichs, 1849) Systematic clinical and gical characterizations of the disease, and the name
patholo-“la sclerose en plaques” were provided by Charcot(1868) Comprehensive reviews of contemporaryclinical and pathological observations were pub-lished by Charcot’s pupils, Bourneville and Guerard(1869) and Bourneville (1892) The subsequentdevelopment of microscopic techniques resulted inthorough analyses of inflammation, demyelination,and neuronal injury in the central nervous system(CNS), whereas advances in neurophysiology led
to a better understanding of the protean clinical presentations of the disease The etiology of MS,however, appeared elusive and most investigatorsexplored toxic or microbial causes (Dejong, 1970)
Autoimmunity as a prevailing hypothesis arose inthe early twentieth century, when postvaccinalleukoencephalitis was observed in a proportion ofpatients who received vaccines against viral diseases,particularly rabies The complication was initiallyattributed to the attenuated virus grown in rabbitbrains However, when Rhesus macaques injectedwith normal rabbit brain homogenate also developed
a condition similar to postvaccinal leukoencephalitis,the autoantigen-triggered and T-cell mediated nature
of the process gained support (Rivers and Schwentker,1935) The animal model became known as experi-mental allergic (or autoimmune) encephalomyelitis(EAE), and it was reproduced in various species forstudying immune-mediated pathways of demyelina-tion After a long-lasting influence of this paradigm,activated myelin-specific T cells are not uniformlyaccepted any more as a primary cause of lesiondevelopment in typical MS Several alternative hypo-theses of etiology are under investigation, but no deci-sive conclusion has been reached (Lassmann, 2005)
The inspiring development of biotechnology and the resultant extraordinary amount of information
in molecular immunology and genetics, clinical neurology, pathology, and imaging, are expected toreveal new correlations of data and a better under-standing of MS pathogenesis Classical natural his-tory data serve today as reference information forevaluating disease heterogeneity and the response
to therapy (Krementchutzky et al., 1999, 2006).The first disease-modifying drug was approved by theFood and Drug Administration (FDA) in 1993 (TheIFNB Multiple Sclerosis Study Group, 1993) Sincethen, the methodology of designing, monitoring,and interpreting clinical trials has itself evolved into
a new science while numerous new pharmaceuticalagents were developed and tested Novel strategiesalso continuously emerge in the area of moleculartherapies (Imitola et al., 2006; Polman et al., 2006;Rudick et al., 2006a)
The following sections summarize the most up-to-date observations concerning epidemiologyand genetics, immune pathogenesis, histology, clin-ical and paraclinical features, and current therapies
of MS and related immune-mediated disorders in the CNS
3.1 Epidemiology and genetics (Bernadette Kalman)
Epidemiology
Epidemiological data of MS have accumulated sincethe early twentieth century Davenport (1922) andLimburg (1950) demonstrated that a geographicdistribution of MS exists A north to south gradientwas noted on the northern hemisphere includingEurope, North America, and Japan (Kurtzke, 1975a,b,1993; Kuroiwa et al., 1983), while a south to northgradient was observed in Australia and New Zealand
on the southern hemisphere (McLeod et al., 1994;Miller et al., 1990; Skegg et al., 1987) Prevalencesurveys from the 1960s to date distinguished highprevalence (30 or more / 100,000, e.g north, western,
3 Multiple sclerosis
Bernadette Kalman
Trang 930 BERNADETTE KALMAN ET AL.
Table 3.1 Epidemiological studies support both environmental and genetic etiology of MS.
Evidence for environmental factors
MS in immigrants occurs with a rate similar
to that in the indigenous population when the immigration is before teenage years Epidemics of MS (e.g on the Faroe Islands) Increasing prevalence and decreasing age
of onset of MS in populations with stable genetics
Evidence for genetic factors
• Ethnic groups (genetic isolates) with varying susceptibility to MS
• Increased familial recurrence
• Higher concordance in monozygotic than in dizygotic twins
• Higher risk for MS in full-sibs than in half-sibs; the presence of a maternal parental effect
• Highly increased risk of MS in siblings of index cases from consanguineous parents
• A similar risk of MS for nonbiological relatives and individuals in the general population
and central Europe), medium (5 –29/100,000, e.g
south Europe) and low prevalence regions (less than5/100,000, e.g most Asian countries) (Kurtzke,2005) These distributions may be related to bothenvironmental (climate, viruses, UV irradiation, anddiet) and genetic factors (Table 3.1)
Migration studies, history of epidemics, and serialepidemiological updates support the existence ofenvironmental effects European immigrants in SouthAfrica develop MS with a similar frequency as theindigenous population, while an opposite trend isobserved for offspring of individuals immigratingfrom India, South Africa, and the West Indies to theUnited Kingdom (Dean, 1967; Elian et al., 1990) Amigration before mid-teenage years seems to confer
to the migrant the recipient country’s risk for MS,possibly related to the effects of childhood infections
on immune maturation (Alter et al., 1966)
MS occurred on the Faroe Islands in four demics between 1943 and 1990 These epidemicswere attributed to a primary infectious agent importedinto the islands by the occupying British forces duringWorld War II, and to its transmission to subsequentgenerations (Kurtzke 1975a,b, 1993, 2005)
epi-Serial epidemiological updates suggest that therelative risk for MS is increasing in certain groups overtime (Kurztke, 2005) This observation is well illus-trated in Sardinia, where the mean annual incidencerate significantly increased from 1.1/100,000 in
1965 – 9 to 5.8/100,000 in 1995 – 9 (Pugliatti et al.,2005) Estimates of MS in cohorts from World War IIand the Korean conflict show a relative risk of 0.44for African American men and 0.22 for other men ascompared to white men, while estimates in similar
ethnic cohorts from the Vietnam war and up to 1994reveal a relative risk of 0.67 and 0.3, respectively(Kurtzke, 2005) The risk of MS for white women ascompared to white men was 1.79 in the earlier cohorts,which also significantly increased in the more recentcohorts Women of all races now have a risk ratio near
to 3:1 as compared to white men (Kurtzke, 2005).Anticipation of age at onset may be another indic-ator for the involvement of environmental factors.Anticipation was demonstrated in two-generational
MS families and longitudinal surveys of sporadic cases
in Sardinia, where the mean age of onset decreasedfrom the most remote to the most recent decade ofbirth from 41 to 21 years (Cocco et al., 2004) Inter-estingly, in another subset of the Sardinian popula-tion an increasing age of onset was noted (Pugliatti
et al., 2005)
In contrast to data supporting the involvement ofenvironmental effects, ethnic, family, and twin studiessuggest the involvement of genetic factors in MS(Table 3.1) While the highest prevalence rates (100/100,000 and beyond) correlate with the worldwidedistribution of individuals of Scandinavian descent(Poser, 1994), several ethnic isolates with resistance
to MS live in geographic locations where the disease
is generally common Examples include gypsies inHungary (Gyodi et al., 1981), Indians and Orientals
in North America (Ebers, 1983; Kurtzki et al., 1979),Lapps in Scandinavia (Gronning and Mellgren, 1985),Maoris in New Zealand (Skegg et al., 1987) andAborigines in Australia (McLeod et al., 1994) Thevarying prevalence rates of MS in the genetically dis-tinct but geographically close populations of Malta,Sicily, and Sardinia also implicate genetic factors
Trang 10Multiple sclerosis 31
(Elian et al., 1987; Rosati 1986) In addition, someethnic groups (e.g Orientals and African Blacks) arecharacterized by very low occurrence of MS (Dean,1967; Poser, 1994)
Familial recurrence of MS was recognized longago (Eichorst, 1896) The observed inheritance pat-terns are incompatible with Mendelian autosomaldominant, recessive, and X-linked or mitochondrialtransmission patterns MS is a complex trait disorderwith the involvement of several genes, each exertingsmall effect, and probably in an interaction with theenvironment There is an excess in the mother-to-child
as compared to the father-to-child transmissions infamilies with vertical concordance (Sadovnick et al.,1991) The age-adjusted empirical recurrence riskfor first-degree relatives is 3 to 5%, which is 30 to
50 times the 0.1% rate in the general population(Sadovnick et al., 1991, 1998) Individuals with agreater “genetic loading” have an earlier age of onset,and “genetic loading” is increased in individualswith affected parents (Sadovnick et al., 1998) In apopulation-based analysis of MS index cases andtheir siblings whose parents were related, Sadovnick
et al (2001) found a recurrence risk of 9% for sibs,which is significantly higher than the risk for sibs of
MS index cases from nonconsanguineous parents
Data from several large twin studies consistentlydemonstrated a higher concordance rate of MSamong monozygotic (21.05% to 40%) as compared
to dizygotic twins (0 to 4.7%), strongly suggesting agenetic effect (Bobowick et al., 1978; Hansen et al.,2005; Heltberg and Holm, 1982; Kinnunen et al.,1988; Mumford et al., 1994; Sadovnick et al., 1993)
The concordance rate among dizygotic twins (4.7%)
is similar to that observed among siblings (5.1%)(Sadovnick et al., 1993)
Further confirmation of genetic effects is gainedfrom studies on adoptees revealing that the frequency
of MS among first-degree nonbiological relatives living with an index case is not greater than expectedfrom the general population (Ebers et al., 1995) Thelargest half-sib study (Ebers et al., 2004) defines anage adjusted recurrence risk of 3.11% and 1.89% for full-siblings and half-siblings, respectively Themoderately significant excess of maternal vs pater-nal half-sibling risk (2.35% vs 1.31%, respectively)suggests a maternal effect on susceptibility to MS
Early case–control candidate gene association studies
Associations of MS with polymorphic alleles of candidate genes involved in immune regulation andmyelin production have been extensively investigatedbased on the autoimmune hypothesis of demyelina-tion (Table 3.2) The first association noted with thehaplotype of class I human leukocyte antigen (HLA)A3 and B7 alleles was extended to the Class II DR2allele in both population and family studies ( Jersild
et al., 1973; Stewart et al., 1979) Since then, theassociation of MS with the HLA A3, B7, DR2, Dw2haplotype has been the most consistent finding
in Caucasians (Francis et al., 1991; Gyodi et al.,1981; Olerup and Hillert, 1991), while HLA DR4was detected in Sardinians and Jordanian Arabs,and DR6 was described in Japanese and Mexicans(Gorodezky et al., 1986; Kurdi et al., 1977; Marrosu
et al., 1988; Naito et al., 1978) Further studiesrevealed that the DR15, DQ6 alleles define the MS-associated DR2, DW2 haplotype, which is describedtoday in DNA-based terminology as DRB1*1501,DQA1*0102, DQB1*0602 haplotype (Hillert et al.,
Table 3.2 Studies in MS.
Region of interest Approach Major finding
Case–control association
Polymorphic alleles of candidate genes Hypothesis-based MHC DRB1 alleles define a major proportion of genetic susceptibility and resistance
LD mapping
Full genome or regional scans Hypothesis-free or
hypothesis-directed Distribution of LD genome wide; identification of chromosomal segments carrying MS susceptibility genes and variants in progress
Trang 1132 BERNADETTE KALMAN ET AL.
1994) Whether the primary MS-specific allele is theDRB1*1501 or the DQB1*0602 could not be sortedout because of the strong linkage disequilibrium (LD) in this region However, recent family and case–
control studies in African Americans suggested aselective association of MS with the DRB1*1501allele and a primary role for the DRB1 locus Thisfinding appeared unlikely to be secondary to anadmixture with Caucasians, since several AfricanAmerican MS susceptibility haplotypes were foundwithin chromosomal segments of African origin(Oksenberg et al., 2004)
Additional studies in the major ity complex (MHC or HLA) region tested the associa-tion of polymorphic alleles of HLA DP (Roth et al.,1991), complement C4, Bf, C2 components (MHC III)(Hauser et al., 1989), protein transporters (LMP,TAP1, TAP2) (Bell and Ramachandran, 1995; Liblau
histocompatibil-et al., 1993) and of the TNF α and TNF β genes with
MS (Braun et al., 1996; Roth et al., 1994) A morphic CA repeat within the gene of myelin oligo-dendrocyte glycoprotein (MOG), telomeric to theMHC, was also tested in MS (Malfroy et al., 1995)(Fig 3.1) However, the overall outcome of thesestudies reflected inconsistent observations and didnot reveal independent associations of MS with genesoutside of the MHC class II subregion (Fig 3.1)
poly-Analyses of sequence variations within germlineelements of the T-cell receptor (TCR) α and β chaingenes as well as tests for a preferential utilization
of certain TCR V–J–D gene segments in the arranged mRNA seemed to reveal promising data
re-in several studies Nevertheless, the re-involvement ofTCR genes in MS susceptibility could not be consis-tently supported (Fugger et al., 1990; Hashimoto
et al., 1992; Oksenberg et al., 1989; Seboun et al.,1989) Linkage analyses also excluded that a TCR
α or β gene would contribute to MS susceptibility(Lynch et al., 1991, 1992) Similarly, both associa-tion and linkage studies of immunoglobulin genes
revealed conflicting observations (Feakes et al.,1998; Hashimoto et al., 1993) Additional analyses
of immune response genes included ligands andreceptors in the cytokine, chemokine, and adhesionmolecule networks, but also without unequivovalconclusion (Crusius et al., 1995; Epplen et al., 1997;
He et al., 1998a) Candidates related to myelin production included the myelin basic protein (MBP)promoter, MOG on chromosome 6 and genes ofoligodendrocyte growth factors or their receptors.However, associations or linkage detected in somestudies were not confirmed in subsequent analyses(Boylan et al., 1990; He et al., 1998b; Mertens et al.,1998; Wood et al., 1994)
Despite the involved conceptual and technical ficulties (e.g matching controls to patients in order
dif-to avoid population stratification or selecting geneticcandidates), the case–control design continues to be
a widely used approach in MS With the recognition
of more and more intercellular and subcellular ways in pathogenesis, the number of molecular can-didates permanently grows (Achiron et al., 2004;Chiocchetti et al., 2005; Kantarci et al., 2005; Leyva
path-et al., 2005; Michailova path-et al., 2005; Oksenberg andBarcellos, 2005) Today, however, both full-genomescans and expression profiling assist a focused selec-tion of candidates, and a comprehensive list of sequencevariations is provided for association studies by theHuman Genome Project (see below)
Linkage studies
In contrast to the hypothesis-driven case–controlassociation approach, the method of linkage canidentify susceptibility loci genome wide without apreconceived idea of disease pathogenesis (Table 3.2).Four full-genome scans with microsatellite markers
in MS families showed linkage to multiple ibility loci, each with a minor effect (λs= 2) (Ebers
suscept-et al., 1996; Kuokkanen suscept-et al., 1997; The Multiple
DP
0 Centromere
1000
DN DO Class II Class III Class I
DQ DR Hsp TNF HLA-B HLA-C HLA-X HLA-E HLA-H
HLA-A HLA-F
HLA-G MOG
α β
21-OH C4 BFC2
Telomere
kb
Fig 3.1 The figure depicts the MHC class II, class III, and class I regions encompassing 4 MB in chromosome 6p21.3
MS-associated haplotypes have been consistently detected in the DRB1–DQB1 subregion in Caucasians.
Trang 12Multiple sclerosis 33
Sclerosis Genetics Group, 1996; Sawcer et al., 1996)
Among the reported provisional sites, the 6p21,5p15, 5q13, 17q22, and 19q13 regions were con-sistently positive in more than one study Additionalsusceptibility loci at 1q44, 2q35, and 18p11 wererecently suggested (Kenealy et al., 2006) A meta-analysis of combined, raw genotype data of threefull-genome scans underscored the importance of17q11 and 6p21 in MS (The Transatlantic MultipleSclerosis Genetics Cooperative Study, 2001) Withinmany regions with the highest scores, clusters ofimmune regulatory genes are encoded (e.g 6p21 –MHC cluster; 17q11 – β-chemokine cluster) Thereare, however, also loci likely involved in neuro-degeneration An association of the epsilon 4 allele
of the ApoE gene in 19q13 was suggested with both
susceptibility and progression rate of MS in severalstudies, but a recent meta-analysis of availableworldwide data showed negative outcome (Burwick
et al., 2006; Schmidt et al., 2002)
Comprehensive analyses of the MHC region furtherconfirmed its importance in MS While Haines et al
(1998) proposed that linkage to the MHC was limited
to families segregating DR2, Ligers et al (2001) alsodetected linkage to this region in a larger cohort ofDRB1*15-negative families This latter observationled to the conclusion that the DRB1*15 may not bethe only HLA determinant of MS The associationwith DRB1*15 may be secondary to LD with a nearbylocus, or disease susceptibility alleles can be present
in DRB1*15-negative haplotypes Analyses of theDRB1 allelic heterogeneity in a large number of MSfamilies showed the involvement of several suscept-ibility (e.g DRB1*15 and DRB1*17) and protective
(e.g DRB1*14) alleles suggesting trans interactions
among DRB1*15-positive and -negative genotypecombinations (Dyment et al., 2005) Altogether, asso-ciation and linkage studies unambiguously establishedthat MHC class II genotypes determine a major pro-portion of genetic susceptibility and resistance to MS
Further refinements of MS susceptibility loci
by LD mapping
The method of linkage in complex disorders usuallyidentifies large (2 –20 cM) chromosomal regions ofinterest, but does not have the power to confine theseregions to single candidate genes with small effects
For fine mapping, the use of modern associationmethods within linkage-defined chromosomal regions
or the entire genome may be considered The HumanGenome Project provided the means for this new
approach The data revealed that two humangenomes are approximately 99.9% identical, leavingstill millions of different base pairs among the total
of 3.2 billion The 0.1% difference is attributed to thepresence of a single nucleotide polymorphism (SNP)
at approximately every 1000 nucleotides SNPs arenot only responsible for the interindividual pheno-typic differences, but also for the variations in sus-ceptibility to common diseases (Table 3.2, Fig 3.2)(The International SNP MAP Working Group, 2001).Because of the abundance of SNPs, these varia-tions may be used as markers in comprehensiveassociation studies SNP marker alleles align in haplotypes which tend to be inherited together in
a given population This correlation between pairedSNP markers is called LD The genome-wide distribu-tion of LD is influenced by many factors and variesamong ethnic groups A recent study of selectedchromosomal regions revealed that half of the SNP haplotypes are 22 kb or larger in African andAfrican-American samples, and 44 kb or larger inEuropean and Asian samples (Gabriel et al., 2002).However, it is important to note that the distribution
of LD shows great regional variations LD between
a marker allele and a disease-specific allele mayallow us to identify mutations or variants with patho-genic significance if SNP markers are genotypedwith sufficient density in a selected region (e.g in alinkage-defined susceptibility locus) Fewer markersmay be used in a two-stage study, which aims first toidentify the disease-associated haplotypes, and thenattempts (with a more dense marker distribution) toreveal disease-relevant mutations within or in theproximity of these haplotypes (Fig 3.2) Using thisstrategy in the 17q11 region, we first defined andthen refined MS-associated haplotypes in two inde-pendent sets of families Sequence analyses of thesehaplotypes and their flanking regions will reveal ifdisease-causing mutations are present in the co-localizing CC chemokine genes (Vyshkina et al.,2005; Vyshkina and Kalman, 2005)
With a high-density SNP panel encompassing theMHC and flanking genomic regions in over 1100 MSfamilies, Lincoln et al (2005) detected strong asso-ciations with blocks in the class II region, and thestrongest association with the DRB1 Conditioning
on HLA DRB1 found no additional block or SNPassociation independent of the class II genomicregion Thus, this study established that MHC-associated susceptibility in MS is defined by HLA class
II alleles, their interactions, and closely ing variants
Trang 13neighbor-34 BERNADETTE KALMAN ET AL.
Full-genome LD mapping studies are also in progressand are expected to identify novel susceptibility geneswith small effects Mapping by admixture linkagedisequilibrium (MALD) offers another new approachfor the identification of disease-relevant genes withapproximately 100 times fewer SNP markers thanwould be required for whole-genome haplotype scans
This method implies that the genomes of differentethnic groups have chromosomal segments of differ-ent origin due to a historic gene flow between them(e.g African Americans have chromosomal segments
of African as well as European origin) (Smith et al.,2004) The strategy involves the identification of agenomic region from one ancestral population withthe highest occurrence of the disease MALD can beparticularly powerful in finding genes for a diseasethat differs profoundly in frequency among popula-tions Highly informative MALD markers have beenrecently defined (Smith et al., 2004) and successfullyused to identify MS-relevant loci in African Americans(Reich et al., 2005)
In summary, recent genetic data reflect a cant increase in power achieved by the use of newassociation-based methods and densely packed SNPmarkers in MS In addition to the identification of disease-associated allelic variants, further explora-tions of epistatic gene interactions as well as of transcriptional and post-transcriptional regulatory mechanisms are needed to better understand the
signifi-disease pathogenesis and to identify the best targetsfor therapy
Mitochondrial (mt)DNA in MS
A group of corollary studies aimed to clarify chondrial genetics in MS MtDNA is a small (16.5 kb)extranuclear part of the human genome Numerouspoint mutations and deletions in mtDNA have been identified in association with neuromuscularand multiorgan disorders A possible involvement
mito-of mtDNA in MS was postulated because there is ahigher transmission of the disease from mother tochild than from father to child (Sadovnick et al.,1991), and because of the observed association between Leber’s hereditary optic neuropathy (LHON),
a mitochondrial disease, and MS (Harding et al.,1992; Lee et al., 1964) The identification of mtDNAmutations at nt 11,778, 3460, and 14,484 with primary pathogenic significance for blindness madepossible the objective evaluation of the associationbetween MS and LHON (Howell et al., 1991; Johns
et al., 1992; Wallace et al., 1988) Such mutationswere reported in a number of patients with prom-inent optic neuritis (PON) and MS (Flanigan et al.,1993; Harding et al., 1992; Kellar-Wood et al.,1994), while inflammatory demyelination was alsofound in LHON patients more often than expected
by chance (Riordan-Eva et al., 1995) However,
acgt aTgtac gtacgt
acgt acgtac Atacgt
• WHEN A MUTATION ARISES,
IT DOES SO IN A SPECIFIC HAPLOTYPE
• EACH MUTATION CAN BE TRACKED IN A POPULATION
BY IDENTIFYING THE CORRESPONDING ANCESTRAL CHROMOSOMAL SEGMENT ON WHICH IT AROSE