Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity.
Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial per...
| Publicado en: | Brain: A Journal of Neurology Vol. 142; no. 12; pp. 3963 - 3975 |
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| Autores principales: | , , , , , , , , , , , |
| Formato: | research Journal Article |
| Publicado: |
Oxford University Press / USA
Dec2019
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| Acceso en línea: | Ver este registro en EBSCOhost |
| fields | @attributes: recordID: 1 pdfLink: plink: https://search.ebscohost.com/login.aspx?direct=true&db=ccm&AN=140097074&site=ehost-live header: @attributes: shortDbName: ccm uiTerm: 140097074 longDbName: CINAHL Complete uiTag: AN controlInfo: bkinfo: dissinfo: jinfo: jid: 00068950 2RY jtl: Brain: A Journal of Neurology issn: 00068950 maglogo: N pubinfo: dt: Dec2019 vid: 142 iid: 12 pid: 622 pub: Oxford University Press / USA artinfo: ui: 140097074 140097074 NLM31687737 140097074 10.1093/brain/awz323 NLM31687737 140097074 ppf: 3963 ppct: 12 formats: tig: atl: Williams syndrome hemideletion and LIMK1 variation both affect dorsal stream functional connectivity. aug: au: Gregory, Michael D Mervis, Carolyn B Elliott, Maxwell L Kippenhan, J Shane Nash, Tiffany Czarapata, Jasmin B. Prabhakaran, Ranjani Roe, Katherine Eisenberg, Daniel P Kohn, Philip D Berman, Karen F B Czarapata, Jasmin affil: Section on Integrative Neuroimaging, Clinical and Translational Neuroscience Branch, National Institute of Mental Health, Intramural Research Program, National Institutes of Health, Bethesda, MD, USA sug: subj: Williams Syndrome Physiopathology Phosphotransferases Parietal Lobe Physiopathology Nervous System Physiopathology Child, Preschool Female Haplotypes Magnetic Resonance Imaging Human Child Young Adult Williams Syndrome Parietal Lobe Adolescence Male Middle Age Adult Nervous System Validation Studies Comparative Studies Evaluation Research Multicenter Studies Clinical Assessment Tools Questionnaires Social Readjustment Rating Scale Funding Source Child, Preschool: 2-5 years Child: 6-12 years Adolescent: 13-18 years Middle Aged: 45-64 years Adult: 19-44 years Female Male ab: Williams syndrome is a rare genetic disorder caused by hemizygous deletion of ∼1.6 Mb affecting 26 genes on chromosome 7 (7q11.23) and is clinically typified by two cognitive/behavioural hallmarks: marked visuospatial deficits relative to verbal and non-verbal reasoning abilities and hypersocial personality. Clear knowledge of the circumscribed set of genes that are affected in Williams syndrome, along with the well-characterized neurobehavioural phenotype, offers the potential to elucidate neurogenetic principles that may apply in genetically and clinically more complex settings. The intraparietal sulcus, in the dorsal visual processing stream, has been shown to be structurally and functionally altered in Williams syndrome, providing a target for investigating resting-state functional connectivity and effects of specific genes hemideleted in Williams syndrome. Here, we tested for effects of the LIMK1 gene, deleted in Williams syndrome and important for neuronal maturation and migration, on intraparietal sulcus functional connectivity. We first defined a target brain phenotype by comparing intraparietal sulcus resting functional connectivity in individuals with Williams syndrome, in whom LIMK1 is hemideleted, with typically developing children. Then in two separate cohorts from the general population, we asked whether intraparietal sulcus functional connectivity patterns similar to those found in Williams syndrome were associated with sequence variation of the LIMK1 gene. Four independent between-group comparisons of resting-state functional MRI data (total n = 510) were performed: (i) 20 children with Williams syndrome compared to 20 age- and sex-matched typically developing children; (ii) a discovery cohort of 99 healthy adults stratified by LIMK1 haplotype; (iii) a replication cohort of 32 healthy adults also stratified by LIMK1 haplotype; and (iv) 339 healthy adolescent children stratified by LIMK1 haplotype. For between-group analyses, differences in intraparietal sulcus resting-state functional connectivity were calculated comparing children with Williams syndrome to matched typically developing children and comparing LIMK1 haplotype groups in each of the three general population cohorts separately. Consistent with the visuospatial construction impairment and hypersocial personality that typify Williams syndrome, the Williams syndrome cohort exhibited opposite patterns of intraparietal sulcus functional connectivity with visual processing regions and social processing regions: decreased circuit function in the former and increased circuit function in the latter. All three general population groups also showed LIMK1 haplotype-related differences in intraparietal sulcus functional connectivity localized to the fusiform gyrus, a visual processing region also identified in the Williams syndrome-typically developing comparison. These results suggest a neurogenetic mechanism, in part involving LIMK1, that may bias neural circuit function in both the general population and individuals with Williams syndrome. pubtype: Academic Journal doctype: research Journal Article ougenre: Article language: English refInfo: holdings: @attributes: islocal: N |
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