Laboratory of Neurogenetics, Mossakowski Medical Research Institute, Polish Academy of Sciences, 02-106 Warsaw, Poland.
Neurology Department, St. Adalbert Hospital, Copernicus PL, 80-462 Gdansk, Poland.
Genes (Basel). 2021 Nov 17;12(11):1806. doi: 10.3390/genes12111806.
We have performed whole-genome sequencing to identify the genetic variants potentially contributing to the early-onset semantic dementia phenotype in a patient with family history of dementia and episodic memory deficit accompanied with profound semantic loss. Only very rare variants of unknown significance (VUS) have been identified: a nonsense variant c.366C>A/p.Cys122* in plasminogen activator, urokinase (PLAU) and a missense variant c.944C>T/p.Thr315Met in β-site APP-cleaving enzyme 1 (BACE1)-along with known disease-modifying variants of moderate penetrance. Patient-derived fibroblasts showed reduced and elevated mRNA and protein levels compared to control fibroblasts. Successful rescue of mRNA levels by nonsense-mediated mRNA decay (NMD) inhibitor (puromycin) confirmed NMD as the underlying mechanism. This is the first report of the variant with the confirmed haploinsufficiency, associated with semantic dementia phenotype. Our results suggest that rare variants in the and genes should be considered in future studies on early-onset dementias.
我们进行了全基因组测序，以鉴定一位有家族痴呆病史和伴有严重语义缺失的情景记忆缺陷患者的早期发病语义痴呆表型的潜在遗传变异。只发现了非常罕见的意义不明的变异（VUS）：纤溶酶原激活物、尿激酶（PLAU）中的无意义变异 c.366C>A/p.Cys122*和β-位淀粉样前体蛋白裂解酶 1（BACE1）中的错义变异 c.944C>T/p.Thr315Met——以及具有中度外显率的已知疾病修饰变异。与对照成纤维细胞相比，患者来源的成纤维细胞显示 和 mRNA 和蛋白水平降低和升高。用无意义介导的 mRNA 降解（嘌呤霉素）抑制剂成功挽救 mRNA 水平证实了 NMD 是潜在的机制。这是首次报道与语义痴呆表型相关的 变异的杂合不足。我们的结果表明，在未来的早发性痴呆研究中，应考虑 和 基因中的罕见变异。
