PDF(Pubmed)
Abstract：
Succinic semialdehyde dehydrogenase (SSADH) is a mitochondrial enzyme involved in the catabolism of the neurotransmitter γ-amino butyric acid. Pathogenic variants in the gene encoding this enzyme cause SSADH deficiency, a developmental disease that manifests as hypotonia, autism, and epilepsy. SSADH deficiency patients usually have family-specific gene variants. Here, we describe a family exhibiting four different SSADH variants: Val90Ala, Cys93Phe, and His180Tyr/Asn255Asp (a double variant). We provide a structural and functional characterization of these variants and show that Cys93Phe and Asn255Asp are pathogenic variants that affect the stability of the SSADH protein. Due to the impairment of the cofactor NAD+ binding, these variants show a highly reduced enzyme activity. However, Val90Ala and His180Tyr exhibit normal activity and expression. The His180Tyr/Asn255Asp variant exhibits a highly reduced activity as a recombinant species, is inactive, and shows a very low expression in eukaryotic cells. A treatment with substances that support protein folding by either increasing chaperone protein expression or by chemical means did not increase the expression of the pathogenic variants of the SSADH deficiency patient. However, stabilization of the folding of pathogenic SSADH variants by other substances may provide a treatment option for this disease.
摘要：
琥珀酸半醛脱氢酶（SSADH）是参与神经递质γ-氨基丁酸分解代谢的线粒体酶。编码该酶的基因中的致病变异导致SSADH缺乏，表现为肌张力减退的发育性疾病，自闭症,和癫痫。SSADH缺乏症患者通常具有家族特异性基因变异。这里,我们描述了一个展示四种不同SSADH变体的家族：Val90Ala，Cys93Phe，和His180Tyr/Asn255Asp(双变体)。我们提供了这些变体的结构和功能表征，并表明Cys93Phe和Asn255Asp是影响SSADH蛋白稳定性的致病性变体。由于辅因子NAD+结合的损害，这些变体显示高度降低的酶活性。然而,Val90Ala和His180Tyr表现出正常的活性和表达。His180Tyr/Asn255Asp变体作为重组物种表现出高度降低的活性，处于非活动状态，并且在真核细胞中显示非常低的表达。通过增加伴奏蛋白表达或通过化学手段支持蛋白折叠的物质的治疗没有增加SSADH缺乏症患者的致病变体的表达。然而,通过其他物质稳定致病性SSADH变体的折叠可能为该疾病提供治疗选择。
