Dorsal visual stream and LIMK1: hemideletion, haplotype, and enduring effects in children with Williams syndrome.
Dorsal stream
Hemideletion
Intraparietal sulcus
LIMK1
Williams syndrome
Journal
Journal of neurodevelopmental disorders
ISSN: 1866-1955
Titre abrégé: J Neurodev Disord
Pays: England
ID NLM: 101483832
Informations de publication
Date de publication:
26 08 2023
26 08 2023
Historique:
received:
06
04
2023
accepted:
04
07
2023
medline:
28
8
2023
pubmed:
27
8
2023
entrez:
26
8
2023
Statut:
epublish
Résumé
Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed "hypersociability") and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS. We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5-22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population. IPS structural (p < 10 This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.
Sections du résumé
BACKGROUND
Williams syndrome (WS), a rare neurodevelopmental disorder caused by hemizygous deletion of ~ 25 genes from chromosomal band 7q11.23, affords an exceptional opportunity to study associations between a well-delineated genetic abnormality and a well-characterized neurobehavioral profile. Clinically, WS is typified by increased social drive (often termed "hypersociability") and severe visuospatial construction deficits. Previous studies have linked visuospatial problems in WS with alterations in the dorsal visual processing stream. We investigated the impacts of hemideletion and haplotype variation of LIMK1, a gene hemideleted in WS and linked to neuronal maturation and migration, on the structure and function of the dorsal stream, specifically the intraparietal sulcus (IPS), a region known to be altered in adults with WS.
METHODS
We tested for IPS structural and functional changes using longitudinal MRI in a developing cohort of children with WS (76 visits from 33 participants, compared to 280 visits from 94 typically developing age- and sex-matched participants) over the age range of 5-22. We also performed MRI studies of 12 individuals with rare, shorter hemideletions at 7q11.23, all of which included LIMK1. Finally, we tested for effects of LIMK1 variation on IPS structure and imputed LIMK1 expression in two independent cohorts of healthy individuals from the general population.
RESULTS
IPS structural (p < 10
CONCLUSIONS
This work offers insight into neurobiological and genetic mechanisms responsible for the WS phenotype and also more generally provides a striking example of the mechanisms by which genetic variation, acting by means of molecular effects on a neural intermediary, can influence human cognition and, in some cases, lead to neurocognitive disorders.
Identifiants
pubmed: 37633900
doi: 10.1186/s11689-023-09493-x
pii: 10.1186/s11689-023-09493-x
pmc: PMC10464045
doi:
Substances chimiques
LIMK1 protein, human
EC 2.7.11.1
Lim Kinases
EC 2.7.11.1
Banques de données
ClinicalTrials.gov
['NCT01132885', 'NCT00004571', 'NCT00001486']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, N.I.H., Intramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
29Subventions
Organisme : NIMH NIH HHS
ID : RC2 MH089924
Pays : United States
Organisme : NIMH NIH HHS
ID : RC2 MH089983
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA MH002863
Pays : United States
Organisme : Intramural NIH HHS
ID : ZIA MH002942
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS035102
Pays : United States
Organisme : NICHD NIH HHS
ID : R37 HD029957
Pays : United States
Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
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