背景:威廉姆斯综合征(WS),由染色体带7q11.23中〜25个基因的半合子缺失引起的罕见神经发育障碍,为研究明确描述的遗传异常和明确表征的神经行为特征之间的关联提供了一个特殊的机会。临床上,WS的典型特征是社交驱动力增加(通常称为“超社交能力”)和严重的视觉空间结构缺陷。先前的研究已将WS中的视觉空间问题与背侧视觉处理流的改变联系起来。我们调查了LIMK1的半端化和单倍型变异的影响,LIMK1是一种在WS中半端化的基因,与神经元成熟和迁移有关。背流的结构和功能,特别是顶内沟(IPS),已知在患有WS的成年人中改变的区域。
方法:我们使用纵向MRI在一个发展中的WS儿童队列中测试了IPS结构和功能的变化(来自33名参与者的76次访问,与94名年龄和性别匹配的参与者的280次访视相比),年龄在5-22岁之间。我们还对12名罕见的患者进行了MRI研究,在7q11.23时出现较短的偏流,所有这些都包括LIMK1。最后,我们在来自普通人群的两个独立健康个体队列中测试了LIMK1变异对IPS结构和估算的LIMK1表达的影响.
结果:先前在成人中报告的IPS结构(p<10-4FDR校正)和功能(p<0.05FDR校正)异常在患有WS的儿童中得到证实,and,符合持久的遗传机制,从童年早期到成年都很稳定。在短暂的偏瘫队列中,发现了与WS类似的IPS缺陷,尽管在结构和功能方面的效应大小均小于WS中发现的效应大小。最后,在按LIMK1单倍型分层的两个普通人群队列中,IPS灰质体积(发现<0.05SVC,预折叠=0.0015)和估算的LIMK1表达(发现=10-15,预折叠=10-23)根据LIMK1单倍型而变化。
结论:这项工作提供了对WS表型负责的神经生物学和遗传机制的见解,并且更广泛地提供了一个惊人的例子,说明了遗传变异的机制。通过分子效应作用于神经中介,可以影响人类的认知,在某些情况下,导致神经认知障碍。
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 < 10-4 FDR corrected) and functional (p < .05 FDR corrected) anomalies previously reported in adults were confirmed in children with WS, and, consistent with an enduring genetic mechanism, were stable from early childhood into adulthood. In the short hemideletion cohort, IPS deficits similar to those in WS were found, although effect sizes were smaller than those found in WS for both structural and functional findings. Finally, in each of the two general population cohorts stratified by
LIMK1 haplotype, IPS gray matter volume (pdiscovery < 0.05 SVC, preplication = 0.0015) and imputed
LIMK1 expression (pdiscovery = 10-15, preplication = 10-23) varied according to
LIMK1 haplotype.
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.