U. Bellugi et al. (1999) - Duke-UNC Brain Imaging and Analysis Center

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P ERSPECTIVES ON DISEASEU. Bellugi et al. – Linking cognition and the brainABCWMS (173) WMS (117)WMSWMSLNdTHLNvNormalNormalspared, while spatial-integrative functions aremarkedly impaired). Perhaps cortical systems that subservethe slower, but higher resolution, processes associatedwith the parvocellular pathway are selectivelyspared in WMS, while in DNS the two pathways couldboth be affected 54 .Brain cytoarchitectonic findings in WMSLNdLNvFig. 7. Brain cytoarchitectonic in Williams syndrome (WMS). (A) Thearrows indicate a marked indentation of the temporo–parietal regionsin the area of the sulcus. The whole posterior-parietal regions andoccipital regions are small. (B) Amygdalar nuclei in WMS and normalbrains, showing that in WMS the dorsal portion of the lateral nucleus(LNd) appears to be reduced and has an unusual shape. The arrowindicates a curtailment in the lateral nucleus of the amygdala. In thisspecimen, the nucleus was estimated to be about half the size of theaverage amygdala in normal subjects. Also, note that the temporalhorn (TH) is placed more dorsally in WMS individuals than in normalsubjects. (C) Unlike in the normal brain, where the central sulcusreaches to the interhemispheric fissure and proceeds a variable distancealong the medial surface of the hemisphere (arrows), the central sulcusin the WMS brain ends substantially before it reaches the midline(arrows). Abbreviation: LNv, ventral lateral nucleus.An opportunity to link brain findings with cognitivedeficits can also be found in the study of focalcognitive deficits of individuals with WMS at the levelof brain cytoarchitectonics. Four autopsy brains ofindividuals with WMS have been studied byGalaburda and colleagues 55–57 (see Fig. 7). Microencephalyand the relative curtailment of the occipitaland posterior-parietal areas were evident in three ofthe brains (Fig. 7A). One of the four brains showed amarked reduction in the size of the parietal, posteriortemporaland occipital regions in comparison with themore rostral portions of the hemispheres. Theseabrupt and dramatic reductions led to the brainappearing as though a band had constricted its posteriorportions 55 . Another brain showed dramaticreduction in the size of the amygdala (Fig. 7B), whichTHcould be associated with abnormal social behaviorthat occurs in subjects with WMS. The MRI data alsocorroborated the general finding of a reduction in thesize of posterior areas. Curtailment of the dorsal-parietalregions and posterior-temporal areas mightindeed be relevant to the extreme visuo–spatialdeficits seen in individuals with WMS. The four brainsshow largely normal overall sulcal patterns, except forsome simplification of tertiary sulcation and a consistentlynon-opercularized dorsal central sulcus. Thecentral sulci in normal brains reach all the way to theinterhemispheric fissure and then a short distance furtheronto the medial surfaces of the hemispheres, butin all the available WMS cases the central sulcus ends noless than a centimeter lateral to the interhemisphericfissure (Fig. 7C). This finding could indicate abnormaldevelopment of the medio–dorsal cortices, whichhave been associated with visuo–spatial functions.The blocks of the cerebral cortex of WMS individualsthat have been examined show well-developedcytoarchitectonic areas with all main divisions identifiable.However, there are subtle distortions in thearchitecture. Morphometric studies suggest that neuronal-cell-packingdensity is diminished with a concurrentincrease in glial numbers, which possibly indicatesa substantial decrease in total number of neurons.The observed cell numbers and cell-packing densitiessuggest early developmental arrest (for example, prenatallyor before the second year of age), or regressiveevents that occur postnatally into the middle of thefirst decade of life 55 . Research that involves establishinglinks between the genomic changes and the changes inproduction of mRNA and protein that lead to theunusual development of the WMS brain, might shedlight on normal brain and behavioral development 56,57 .In general, these findings provide unusual opportunitiesfor linking brain findings to cognitive deficitsand their neural underpinnings.A molecular-genetic profile for WMSWilliams syndrome is caused by a microdeletion onchromosome 7 that involves the gene encodingelastin (ELN) 58 and perhaps 20 other genes, includingthe human homolog of the Drosophila gene, frizzled(FZD3) 59 , LIM-kinase 1 (LIMK1) 60 , syntaxin 1A (STX1A) 61 ,replication factor C2 (RFC2) 62 , CLYNZ (Ref. 63), FKPB6(Ref. 64), WSTF (Ref. 65), WS-bTRP, WS-bHLH, BCL7B(Ref. 66), and a duplicated gene, GTF2I (general transcriptionfactor 2I) 67 . Korenberg and colleagues areconstructing a physical map of the deleted region ofchromosome 7 band 7q11.23 by using multi-colorfluorescence in situ hybridization (FISH) of bacterialartificial chromosomes (BACs) on metaphase and interphasechromosomes, large-fragment library screening,genomic Southern blot and pulsed-field-gel analyses,STS (sequence tagged site) and polymorphic-markeranalyses. Bacterial artificial chromosomes were chosento construct the physical map because they are clonedin a stable vector and contain large genomic fragmentsof up to 300 kb that are stable and readilymanipulated. Therefore, they are suitable for geneisolation and DNA sequencing. These map reagentswere used to investigate the size and extent of thedeletions in individuals with WMS in whom subsets offeatures, including neurocognitive profiles, brainstructures and brain functions, were determinedsimultaneously 68–70 .204 TINS Vol. 22, No. 5, 1999
Fig. 8. The molecular-genetic basis ofWilliams syndrome (WMS). (A) The region ofchromosome 7, band 7qll.23, that is commonlydeleted in WMS is represented by thedark-blue box in the ideogram. This region isexpanded to the right to illustrate its genomicorganization, a region of mainly single copygenes – the homolog of the Drosophila gene,frizzled (FZD3), syntaxin 1A (STX1A), elastin(ELN), LIM-kinase 1 (LIMK1), WSCR1, replicationfactor C2 (RFC2) – flanked by a seriesof genomic duplications (green, pale blue)containing genes (for example, GTF2I),pseudogenes (for example, GTF2IP, PMS2P),and duplicate markers (for example,D7S489L). The regions used in the commonbreakpoints are indicated by dark-blue bars.The map positions of independent bacterialartificial chromosomes (BACs) used in part forthis analysis are shown as green dots to theleft of the ideogram. (B) Vertical lines indicatethe regions deleted and the number of subjectscarrying the common WMS deletion,which are associated with some of the typicalfacial features, mental retardation and heartdisease, or carrying smaller deletions, includingsubregions of STX1A through to RFC2,which are associated with only the typicalheart disease, SVAS. Subject VI also has asubtle defect in visual–spatial processing.Small square brackets indicate deleted regionsthat differ among subjects and, therefore,provide the potential deletion to assign specificWMS features to single regions or genes.The large square brackets indicate regionsthat, from the current data, are likely to containa gene or genes that when deleted contributein some measure to the characteristicfeatures of WMS. The significance of thesedata is that deletion of STX1A, ELN, LIMK1,WSCR1 and RFC2 do not appear to be associatedwith the characteristic facial features ormental retardation seen in WMS, althoughthey could contribute. This is the first step indefining single genes whose deletion is ultimatelyresponsible for the distinctive cognitivefeatures of WMS. Subject I is a typical WMSindividual 67,68,71,74,75 , subject II has a largerdeletion than a typical WMS individual 71,76 ,subject III can be found in the Italian casesdetailed in Ref. 69, details of subjects IV andV can be found in Ref. 77, and details of subjectsVI and VII can be found in Refs 78 and60, respectively.A working model of the genomeorganization that characterizeschromosome band 7q11.2 andincorporates other maps 71,72 was developed 73 and itsuggests that this region includes highly homologouschromosomal duplications that are also characterizedby a number of repeat-sequence families, genes andpseudogenes. The totality is organized as a nestedrepeated structure that surrounds the largely uniqueregion occupied by elastin and the other deleted genes(Fig. 8A). This suggests that the region of DNA deletedin WMS individuals is located within an apparentlysingle copy region of chromosome 7 that appears to besurrounded by a series of genomic duplications, someof which must be recent and others of which mighthave been duplicated earlier in primate evolution.ABChromosome7222115.315.215.114131211.211.111.111.2111.2211.2321.121.221.32231.131.231.33233343536GenesBACsD7S653D7S489UFZD3STX1AELNLIMK1WSCR1RFC2U. Bellugi et al. – Linking cognition and the brain P ERSPECTIVES ON DISEASEChromosome7222115.315.114131211.111.111.2211.2321.121.221.32231.131.231.3GTF2I146 2D7S489L 2D7S6753233343536WMS1GTF2IPPMS2PD7489UFZD3STX1AELNLIMK1WSCR1RFC2GTF2ID7S489LPMS2PSVASI II III IV V VI VIISubject2DuplicatedregionsMeiotic mispairing of subsets of the numerousrepeated sequences might ultimately contribute to thedeletion 71 . Therefore, it is not unexpected that thedeletion breakpoints in WMS occur largely in commonregions and most, though not all, individualswith WMS have the same genes deleted 68,71,74 .However, it is studies of the uncommon individualswith smaller deletions that are beginning to provideclues to the genes responsible for the subsets of WMS features.For example, from studies of individuals with isolateddeletions and mutations of elastin, it appears thatthe absence of one copy of the gene is probably responsiblefor the heart defect, SVAS, that is typically found in11PhenotypesBreakpointWMSdeletionBreakpointSome WMS MRI andcognitive featuresSome WMS facialfeaturesHeart diseaseSome visuo–spatialfeaturesNormal IQSome WMS MRI andcognitive featuresSome WMS facialfeaturesTINS Vol. 22, No. 5, 1999 205
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U. Bellugi et al. (1999) - Duke-UNC Brain Imaging and Analysis Center

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