Background

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.

Methods

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.

Results

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.

Conclusions

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.

中文翻译：

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PDZD8 破坏导致人类、小鼠和果蝇的认知障碍

背景

发现赋予智力障碍 (ID) 风险的基因编码变异是了解这种常见发育障碍的病理生理学的重要一步。

方法

纯合子作图、全外显子组测序和共分离分析用于鉴定来自阿拉伯半岛的两个独立近亲家庭中导致具有自闭症特征的综合征 ID 的基因变异。对于相关基因在认知中的功能的体内功能研究，使用了黑腹果蝇和具有直系同源基因靶向干扰的小鼠。对表型测试进行了行为、电生理和结构磁共振成像分析。

结果

PDZD8中的纯合提前终止密码子编码内质网锚定的脂质转移蛋白，在两个家族中都显示出与综合征 ID 的共分离。敲除PDZD8直系同源物的黑腹果蝇表现出基于求偶的长期记忆受损。Pdzd8中提前终止密码子的纯合小鼠表现出大脑结构、海马空间记忆和突触可塑性缺陷。

结论

这些数据表明PDZD8中的纯合功能丧失突变与神经发育性认知障碍有关。操纵直系同源基因的模型生物复制了人类表型的各个方面，并提出了以破坏大脑发育和突触功能为中心的合理病理生理机制。因此，这些发现与越来越多的证据一致，即突触缺陷是 ID 和其他神经发育状况的共同特征。