Biallelic variants in HPDL , encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition,Genetics in Medicine

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Biallelic variants in HPDL , encoding 4-hydroxyphenylpyruvate dioxygenase-like protein, lead to an infantile neurodegenerative condition
Genetics in Medicine ( IF 8.8 ) Pub Date : 2020-11-14 , DOI: 10.1038/s41436-020-01010-y
Shereen G Ghosh _{1,

2} , Sangmoon Lee _{1,

2} , Rudy Fabunan ₃ , Guoliang Chai _{1,

2} , Maha S Zaki ₄ , Ghada Abdel-Salam ₄ , Tipu Sultan ₅ , Tawfeg Ben-Omran ₆ , Javeria Raza Alvi ₅ , Jennifer McEvoy-Venneri _{1,

2} , Valentina Stanley _{1,

2} , Aakash Patel _{1,

2} , Danica Ross _{1,

2} , Jeffrey Ding ₇ , Mohit Jain ₇ , Daqiang Pan ₈ , Philipp Lübbert ₉ , Bernd Kammerer ₈ , Nils Wiedemann _{9,

10} , Nanda M Verhoeven-Duif ₁₁ , Judith J Jans ₁₁ , David Murphy ₁₂ , Mehran Beiraghi Toosi ₁₃ , Farah Ashrafzadeh ₁₄ , Shima Imannezhad ₁₅ , Ehsan Ghayoor Karimiani _{16,

17} , Khalid Ibrahim ₁₈ , Elizabeth R Waters ₃ , Reza Maroofian _{19,

20} , Joseph G Gleeson _{1,

2}

Affiliation

Department of Neurosciences, University of California-San Diego, La Jolla, CA, USA.
Rady Children's Institute for Genomic Medicine, San Diego, CA, USA.
Biology Department, San Diego State University, San Diego, CA, USA.
Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
Department of Pediatric Neurology, Institute of Child Health, Children Hospital Lahore, Lahore, Pakistan.
Division of Genetic and Genomic Medicine, Sidra Medicine and Hamad Medical Corporation, Doha, Qatar.
Departments of Medicine and Pharmacology, University of California-San Diego, La Jolla, CA, USA.
Centre for Integrative Signalling Analysis (CISA), University of Freiburg, Freiburg, Germany.
Institute of Biochemistry and Molecular Biology, ZBMZ, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
CIBSS Centre for Integrative Biological Signalling Studies, University of Freiburg, Freiburg, Germany.
Section Metabolic Diagnostics, Department of Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
Department of Clinical and Movement Neurosciences, UCL Institute of Neurology, Queen Square, London, UK.
Pediatric Neurology Department, Ghaem Hospital, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pediatrics, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Department of Pediatric Neurology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
Molecular and Clinical Sciences Institute, St. George's, University of London, Cranmer Terrace, London, UK.
Innovative Medical Research Center, Mashhad Branch, Islamic Azad University, Mashhad, Iran.
Division of Pediatric Neurology, Sidra Medicine, Doha, Qatar.
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University, London, UK.
Department of Neuromuscular Disorders, UCL Institute of Neurology, Queen Square, London, UK.

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.

中文翻译：

HPDL 中的双等位基因变异，编码 4-羟基苯丙酮酸双加氧酶样蛋白，导致婴儿神经退行性疾病

目的

双加氧酶是氧化还原酶，在有氧生活所必需的代谢途径中发挥作用。由HPDL编码的 4-羟基苯基丙酮酸双加氧酶样蛋白 (HPDL)是 4-羟基苯基丙酮酸双加氧酶 (HPD) 的孤儿旁系同源物，它是一种参与酪氨酸分解代谢的铁依赖性双加氧酶。HPDL 与人类疾病的功能和关联仍然未知。

方法

我们在超过 10,000 名患有神经发育疾病的个体中应用了外显子组测序。通过质谱分析在体外和体内研究了 HPDL 损失的影响。进行进化分析以研究 HPDL 与 HPD 的潜在功能分离。

结果

我们在八个显示隐性遗传的家族中鉴定了HPDL中的双等位基因变体。敲除小鼠与人类密切地进行表型复制，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是一种单外显子基因，可能源于四足动物谱系底部的逆转录转座事件，与 HPD 不同，HPDL 是线粒体定位的。HPDL突变细胞和小鼠的代谢谱未显示酪氨酸代谢物改变的证据，而是在其他代谢途径中显着积累。