Abstract：
To investigate the genotype-to-protein-to-phenotype correlations of succinic semialdehyde dehydrogenase deficiency (SSADHD), an inherited metabolic disorder of γ-aminobutyric acid catabolism. Bioinformatics and in silico mutagenesis analyses of ALDH5A1 variants were performed to evaluate their impact on protein stability, active site and co-factor binding domains, splicing, and homotetramer formation. Protein abnormalities were then correlated with a validated disease-specific clinical severity score and neurological, neuropsychological, biochemical, neuroimaging, and neurophysiological metrics. A total of 58 individuals (1:1 male/female ratio) were affected by 32 ALDH5A1 pathogenic variants, eight of which were novel. Compared to individuals with single homotetrameric or multiple homo and heterotetrameric proteins, those predicted not to synthesize any functional enzyme protein had significantly lower expression of ALDH5A1 (p = 0.001), worse overall clinical outcomes (p = 0.008) and specifically more severe cognitive deficits (p = 0.01), epilepsy (p = 0.04) and psychiatric morbidity (p = 0.04). Compared to individuals with predictions of having no protein or a protein impaired in catalytic functions, subjects whose proteins were predicted to be impaired in stability, folding, or oligomerization had a better overall clinical outcome (p = 0.02) and adaptive skills (p = 0.04). The quantity and type of enzyme proteins (no protein, single homotetramers, or multiple homo and heterotetramers), as well as their structural and functional impairments (catalytic or stability, folding, or oligomerization), contribute to phenotype severity in SSADHD. These findings are valuable for assessment of disease prognosis and management, including patient selection for gene replacement therapy. Furthermore, they provide a roadmap to determine genotype-to-protein-to-phenotype relationships in other autosomal recessive disorders.
摘要：
探讨琥珀酸半醛脱氢酶缺乏症(SSADHD)基因型与蛋白表型的相关性,γ-氨基丁酸分解代谢的遗传性代谢紊乱。进行了ALDH5A1变体的生物信息学和硅诱变分析，以评估它们对蛋白质稳定性的影响。活性位点和辅因子结合域，拼接,和同源四聚体的形成。然后将蛋白质异常与经过验证的疾病特异性临床严重程度评分和神经系统相关，神经心理学，生物化学，神经影像学,和神经生理学指标。共有58名个体（1：1的男女比例）受到32种ALDH5A1致病性变异的影响，其中八个是小说。与具有单个同源四聚体或多个同源和异源四聚体蛋白的个体相比，那些预测不合成任何功能酶蛋白的ALDH5A1的表达显着降低（p=0.001），总体临床结果较差（p=0.008），尤其是更严重的认知障碍（p=0.01），癫痫（p=0.04）和精神病发病率（p=0.04）。与预测没有蛋白质或催化功能受损的蛋白质的个体相比，预测蛋白质稳定性受损的受试者，折叠,或寡聚化具有更好的总体临床结局(p=0.02)和适应性技能(p=0.04).酶蛋白的数量和类型(无蛋白质，单同四聚体，或多个同型和异型四聚体)，以及它们的结构和功能损伤(催化或稳定性，折叠,或低聚)，有助于SSADHD的表型严重程度。这些发现对于评估疾病的预后和管理是有价值的。包括基因替代疗法的患者选择。此外，它们为确定其他常染色体隐性遗传疾病的基因型-蛋白质-表型关系提供了路线图.
