Genetic variation of the multi‐zinc finger BTB domain transcription factor ZBTB18 can cause a spectrum of human neurodevelopmental disorders, but the underlying mechanisms are not well understood. Recently, we reported that pathogenic, de novo ZBTB18 missense mutations alter its DNA‐binding specificity and gene regulatory functions, leading to human neurodevelopmental disease. However, the functional impact of the general population ZBTB18 missense variants is unknown. Here, we investigated such variants documented in the Genome Aggregation Database (gnomAD) to discover that ZBTB gene family members are intolerant to loss‐of‐function and missense mutations, but not synonymous mutations. We studied ZBTB18 as a protein–DNA complex to find that general population missense variants are rare, and disproportionately map to non‐DNA‐contact residues, in contrast to the majority of disease‐associated variants that map to DNA‐contact residues, essential to motif binding. We studied a selection of variants (n = 12), which spans the multi‐zinc finger region to find 58.3% (7/12) of variants displayed altered DNA binding, 41.6% (5/12) exhibited altered transcriptional activity in a luciferase reporter assay, 33.3% (4/12) exhibited altered DNA binding and transcriptional activity, whereas 33.3% (4/12) displayed a negligible functional impact. Our results demonstrate that general population variants, while rare, can influence ZBTB18 function, with potential consequences for neurodevelopment, homeostasis, and disease.

中文翻译：

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一般人群 ZBTB18 错义变异影响 DNA 结合和转录调控。

多锌指 BTB 结构域转录因子 ZBTB18 的遗传变异可导致一系列人类神经发育障碍，但其潜在机制尚不清楚。最近，我们报道了致病性、从头ZBTB18 错义突变改变其 DNA 结合特异性和基因调控功能，导致人类神经发育疾病。然而，一般人群 ZBTB18 错义变异的功能影响尚不清楚。在这里，我们调查了基因组聚合数据库 (gnomAD) 中记录的此类变体，以发现 ZBTB 基因家族成员不能容忍功能丧失和错义突变，但不能容忍同义突变。我们研究了 ZBTB18 作为蛋白质-DNA 复合物，发现一般人群错义变异很少见，并且不成比例地映射到非 DNA 接触残基，这与映射到 DNA 接触残基的大多数疾病相关变异形成对比，这对于基序绑定。我们研究了一系列变体（n = 12)，它跨越多锌指区域，发现 58.3% (7/12) 的变异表现出改变的 DNA 结合，41.6% (5/12) 在荧光素酶报告基因检测中表现出改变的转录活性，33.3% (4/ 12) 表现出改变的 DNA 结合和转录活性，而 33.3% (4/12) 表现出的功能影响可以忽略不计。我们的结果表明，一般人群变异虽然罕见，但会影响 ZBTB18 功能，对神经发育、体内平衡和疾病具有潜在影响。