Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition
Biallelic variants in HPDL, encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition
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DOI：
10.1038/s41436-020-01010-y
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发表时间：
2020-11-14
影响因子：
8.8
通讯作者：
Gleeson, Joseph G.
中科院分区：
文献类型：
--
作者：
Ghosh, Shereen G.;Lee, Sangmoon;Gleeson, Joseph G.
目的：双加氧酶是氧化还原酶，在有氧生命所必需的代谢途径中发挥作用。4-羟基苯丙酮酸双加氧酶样蛋白(HPDL)是参与酪氨酸分解代谢的铁依赖双加氧酶4-羟基苯丙酮酸双加氧酶(HPD)的孤儿蛋白。HPDL的功能和与人类疾病的关联仍不清楚。方法我们对10,000多名神经发育疾病患者进行了外显子组测序。通过体内、体外实验和质谱学分析，研究HPDL丢失的影响。进化分析用于研究HPDL和HPD的潜在功能分离。结果在8个隐性遗传家系中发现了HPDL的双等位变异。基因敲除小鼠与人类相似，并在大脑皮层内的多个细胞谱系中显示出细胞凋亡的证据。HPDL是一个单外显子基因，可能起源于四足动物谱系底部的逆转录转座事件，与HPD不同，HPDL定位于线粒体。HPDL突变细胞和小鼠的代谢图谱显示，没有证据表明酪氨酸代谢物发生了变化，但在其他代谢途径中有显著的积累。结论线粒体定位及其代谢紊乱提示人类HPDL缺失与一种独特的神经代谢线粒体婴儿神经退行性疾病有关。
Purpose Dioxygenases are oxidoreductase enzymes with roles in metabolic pathways necessary for aerobic life. 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), encoded by HPDL, is an orphan paralogue of 4-hydroxyphenylpyruvate dioxygenase (HPD), an iron-dependent dioxygenase involved in tyrosine catabolism. The function and association of HPDL with human diseases remain unknown. Methods We applied exome sequencing in a cohort of over 10,000 individuals with neurodevelopmental diseases. Effects of HPDL loss were investigated in vitro and in vivo, and through mass spectrometry analysis. Evolutionary analysis was performed to investigate the potential functional separation of HPDL from HPD. Results We identified biallelic variants in HPDL in eight families displaying recessive inheritance. Knockout mice closely phenocopied humans and showed evidence of apoptosis in multiple cellular lineages within the cerebral cortex. HPDL is a single-exonic gene that likely arose from a retrotransposition event at the base of the tetrapod lineage, and unlike HPD, HPDL is mitochondria-localized. Metabolic profiling of HPDL mutant cells and mice showed no evidence of altered tyrosine metabolites, but rather notable accumulations in other metabolic pathways. Conclusion The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.