Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction
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DOI：
10.1016/j.ajhg.2021.01.007
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发表时间：
2021-02-04
影响因子：
9.8
通讯作者：
Vissers, Lisenka E. L. M.
中科院分区：
文献类型：
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作者：
den Hoed, Joery;de Boer, Elke;Vissers, Lisenka E. L. M.
尽管大规模统计分析可以稳健地识别疾病-基因关系，但它们不能准确捕获基因型-表型相关性或疾病机制。我们使用多条独立证据来表明，单个基因 SATB1 中的不同变异类型会导致临床上重叠但不同的神经发育障碍。对 42 名携带 SATB1 变异体的个体进行的临床评估确定了通过功能测定建立的与不同病理生理机制相关的明显基因型-表型关系。 CUT1 和 CUT2 DNA 结合域中的错义变异会导致更强的染色质结合、增加转录抑制和严重的表型。相反，预计会导致单倍体不足的变异与较温和的临床表现相关。对于具有过早蛋白质截短变体的个体也观察到类似的温和表型，这些变体逃避了无义介导的衰变，这些变体具有转录活性，但在细胞中错误定位。我们的结果表明，深入的突变特异性基因型-表型研究对于全面了解疾病的复杂性并解释表型变异至关重要。
Whereas large-scale statistical analyses can robustly identify disease-gene relationships, they do not accurately capture genotype-phenotype correlations or disease mechanisms. We use multiple lines of independent evidence to show that different variant types in a single gene, SATB1, cause clinically overlapping but distinct neurodevelopmental disorders. Clinical evaluation of 42 individuals carrying SATB1 variants identified overt genotype-phenotype relationships, associated with different pathophysiological mechanisms, established by functional assays. Missense variants in the CUT1 and CUT2 DNA-binding domains result in stronger chromatin binding, increased transcriptional repression, and a severe phenotype. In contrast, variants predicted to result in haploinsufficiency are associated with a milder clinical presentation. A similarly mild phenotype is observed for individuals with premature protein truncating variants that escape nonsense-mediated decay, which are transcriptionally active but mislocalized in the cell. Our results suggest that in-depth mutation-specific genotype-phenotype studies are essential to capture full disease complexity and to explain phenotypic variability.