PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.
PDZD8 Disruption Causes Cognitive Impairment in Humans, Mice, and Fruit Flies.
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DOI：
10.1016/j.biopsych.2021.12.017
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发表时间：
2022-08-15
影响因子：
10.6
通讯作者：
中科院分区：
文献类型：
--
作者：
发现基因编码变异，赋予智力残疾（ID）的风险是一个重要的一步，了解这种常见的发育障碍的病理生理学。纯合性作图，全外显子组测序，共分离分析被用来确定基因变异负责综合征ID与自闭症的特点，在两个独立的血缘家庭从阿拉伯半岛。对于在体内功能研究的牵连基因的功能在认知中，果蝇和小鼠的orthopathy基因的有针对性的干扰。进行行为、电生理和结构磁共振成像分析以进行表型测试。PDZD 8中编码内质网锚定脂质转移蛋白的纯合提前终止密码子在两个家族中均与综合征ID共分离。敲低PDZD 8同源基因的果蝇表现出受损的长期求爱记忆。Pdzd8提前终止密码子纯合子小鼠表现出脑结构、海马空间记忆和突触可塑性缺陷。这些数据证明了PDZD 8中的纯合功能丧失突变参与神经发育性认知障碍。模型生物与操纵的orthopathy基因复制人类表型的方面，并提出合理的病理生理机制，集中在中断大脑发育和突触功能。因此，这些发现与突触缺陷是ID和其他神经发育状况的共同特征的证据一致。
The discovery of coding variants in genes that confer risk of intellectual disability (ID) is an important step toward understanding the pathophysiology of this common developmental disability. Homozygosity mapping, whole-exome sequencing, and cosegregation analyses were used to identify gene variants responsible for syndromic ID with autistic features in two independent consanguineous families from the Arabian Peninsula. For in vivo functional studies of the implicated gene’s function in cognition, Drosophila melanogaster and mice with targeted interference of the orthologous gene were used. Behavioral, electrophysiological, and structural magnetic resonance imaging analyses were conducted for phenotypic testing. Homozygous premature termination codons in PDZD8, encoding an endoplasmic reticulum–anchored lipid transfer protein, showed cosegregation with syndromic ID in both families. Drosophila melanogaster with knockdown of the PDZD8 ortholog exhibited impaired long-term courtship-based memory. Mice homozygous for a premature termination codon in Pdzd8 exhibited brain structural, hippocampal spatial memory, and synaptic plasticity deficits. These data demonstrate the involvement of homozygous loss-of-function mutations in PDZD8 in a neurodevelopmental cognitive disorder. Model organisms with manipulation of the orthologous gene replicate aspects of the human phenotype and suggest plausible pathophysiological mechanisms centered on disrupted brain development and synaptic function. These findings are thus consistent with accruing evidence that synaptic defects are a common denominator of ID and other neurodevelopmental conditions.
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影响因子：
6.8
作者：
Dachtler J;Glasper J;Cohen RN;Ivorra JL;Swiffen DJ;Jackson AJ;Harte MK;Rodgers RJ;Clapcote SJ
通讯作者：
Clapcote SJ
影响因子：
16.6
作者：
Elbaz-Alon, Yael;Guo, Yuting;Nunnari, Jodi
通讯作者：
Nunnari, Jodi
DOI：
10.1093/bfgp/elm022
发表时间：
2007-09-01
期刊：
Briefings in Functional Genomics & Proteomics
影响因子：
--
作者：
Friedel, Roland H.;Seisenberger, Claudia;Wurst, Wolfgang
通讯作者：
Wurst, Wolfgang
影响因子：
64.8
作者：
Karczewski, Konrad J;Francioli, Laurent C;MacArthur, Daniel G
通讯作者：
MacArthur, Daniel G
DOI：
10.1093/cercor/bhv227
发表时间：
2016-01
期刊：
Cerebral cortex (New York, N.Y. : 1991)
影响因子：
--
作者：
Dennis SH;Pasqui F;Colvin EM;Sanger H;Mogg AJ;Felder CC;Broad LM;Fitzjohn SM;Isaac JT;Mellor JR
通讯作者：
Mellor JR