H139Hfs13* PPM1K 导致 MSUD 的轻微变异
中文名称
通路描述
PPM1K 是一种线粒体蛋白磷酸酶，它从丙酮酸脱氢酶复合体（BCKDH）的 E1β亚基上移除抑制性磷酸化，从而恢复 BCKDH 活性（Lu 等，2007; Lu 等，2009a, b; Wynn 等，2012; Zhou 等，2012）。BCKDH 负责丙氨酸、缬氨酸和异亮氨酸衍生物的氧化脱羧，提供乙酰辅酶 A 和琥珀酰辅酶 A 中间体用于 Krebs 循环（综述 Strauss 等，2020; Zhang 等，2023）。BCKDH 亚基的功能丧失突变会导致尿液中积累有毒的丙氨酸、缬氨酸和异亮氨酸衍生物，引起神经缺陷，并导致枫糖尿症（MSUD）。最近，PPM1K 中的移码突变被确定为导致 MSUD 轻微变异的 probable 原因（Oyarzabal 等，2012）。该移码在残基 151 处引入终止密码子，使蛋白质不稳定，并将 PPM1K 缺陷的成纤维细胞系与野生型 PPM1K 的转染恢复 BCKDH 活性（Oyarzabal 等，2012）。
英文描述
H139Hfs13* PPM1K causes a mild variant of MSUD PPM1K is a mitochondrial protein phosphatase that removes the inhibitory phosphorylation from the E1 beta subunit of branched-chain ketoacid dehydrogenase (BCKDH) to restore BCKDH activity (Lu et al, 2007; Lu et al, 2009 a, b; Wynn et al, 2012; Zhou et al, 2012).
BCKDH is responsible for the oxidative decarboxylation of branched-chain amino acid (BCAA) derivatives of leucine, valine and isoleucine, providing acetyl CoA and succinyl CoA intermediates for the Krebs Cycle (reviewed in Strauss et al, 2020; Zhang et al, 2023). Loss-of-function mutations in subunits of BCKDH cause accumulation of toxic BCAAs in the urine, neurological defects and are the cause of Maple Syrup Urine disease (MSUD). More recently, a frameshift mutation in PPM1K was identified as the probable cause of a mild variant of MSUD (Oyarzabal et al, 2012). This frameshift introduces a stop codon at residue 151, destabilizing the protein, and transfection of PPM1K-deficient fibroblast lines with WT PPM1K restores BCKDH activity (Oyarzabal et al, 2012).
BCKDH is responsible for the oxidative decarboxylation of branched-chain amino acid (BCAA) derivatives of leucine, valine and isoleucine, providing acetyl CoA and succinyl CoA intermediates for the Krebs Cycle (reviewed in Strauss et al, 2020; Zhang et al, 2023). Loss-of-function mutations in subunits of BCKDH cause accumulation of toxic BCAAs in the urine, neurological defects and are the cause of Maple Syrup Urine disease (MSUD). More recently, a frameshift mutation in PPM1K was identified as the probable cause of a mild variant of MSUD (Oyarzabal et al, 2012). This frameshift introduces a stop codon at residue 151, destabilizing the protein, and transfection of PPM1K-deficient fibroblast lines with WT PPM1K restores BCKDH activity (Oyarzabal et al, 2012).
所含基因
4 个基因