Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Genet Med. 2021 Mar;23(3):524-533. doi: 10.1038/s41436-020-01010-y. Epub 2020 Nov 14.
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.
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.
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.
The mitochondrial localization, along with its disrupted metabolic profile, suggests HPDL loss in humans links to a unique neurometabolic mitochondrial infantile neurodegenerative condition.
双氧酶是氧化还原酶，在需氧生命的代谢途径中发挥作用。HPDL 编码的 4-羟苯基丙酮酸双加氧酶样蛋白（HPDL）是 4-羟苯基丙酮酸双加氧酶（HPD）的孤儿旁系同源物，HPD 是一种参与酪氨酸分解代谢的铁依赖性双氧酶。HPDL 与人类疾病的功能和关联尚不清楚。
我们在一个超过 10000 名神经发育疾病患者的队列中应用外显子组测序。在体外和体内通过质谱分析研究 HPDL 缺失的影响，并进行进化分析以研究 HPDL 与 HPD 之间潜在的功能分离。
我们在 8 个显示隐性遗传的家族中鉴定出 HPDL 的双等位基因变异。敲除小鼠与人类非常相似，并且在大脑皮层内的多个细胞谱系中显示出凋亡的证据。HPDL 是一个单外显子基因，可能是在四足动物谱系的底部通过反转录转座事件产生的，与 HPD 不同，HPDL 定位于线粒体。HPDL 突变细胞和小鼠的代谢谱分析没有显示出酪氨酸代谢物的改变，但在其他代谢途径中却有明显的积累。
线粒体定位及其代谢谱的破坏表明，人类 HPDL 的缺失与一种独特的神经代谢性婴儿期神经退行性疾病有关。
