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

Ghosh, Shereen G.; Lee, Sang Moon; Fabunan, Rudy; Chai, Guoliang; Zaki, Maha S.; Abdel-Salam, Ghada M H; Sultan, Tipu; Ben‐Omran, Tawfeg; Alvi, Javeria Raza; McEvoy‐Venneri, Jennifer; Stanley, Valentina; Patel, Anjni; Ross, Danica; Ding, Jeffrey; Jain, Mohit; Pan, Daqiang; Lübbert, Philipp; Kammerer, Bernd; Wiedemann, Nils; Verhoeven‐Duif, Nanda M.; Jans, Judith; Murphy, David; Toosi, Mehran Beiraghi; Ashrafzadeh, Farah; Imannezhad, Shima; Karimiani, Ehsan Ghayoor; Ibrahim, Khalid; Waters, Elizabeth R.; Maroofian, Reza; Gleeson, Joseph G.

doi:10.1038/s41436-020-01010-y

Cited by 20 publications

(46 citation statements)

References 36 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In colon adenocarcinoma cells, it has been shown that HPDL KD reduced oxygen consumption, implying that it could play a role in controlling mitochondria functions. Besides, in colon cancer cells, HPDL has been shown to localise to mitochondria and its KO did not result in impaired tyrosine catabolism 33 , suggesting that, similarly to HPD, HPDL could be involved in multiple metabolic pathways. Interestingly, our preliminary evidence suggest that HPDL KD resulted in reduced fumarate levels under amino acid starvation in MDA-MB-231 cells (data not shown).…”

Section: Discussionmentioning

confidence: 99%

The extracellular matrix supports cancer cell growth under amino acid starvation by promoting tyrosine catabolism

Nazemi

Yanes

Martinez

et al. 2021

Preprint

View full text Add to dashboard Cite

Breast cancer tumours are embedded in a collagen I rich extracellular matrix (ECM) network where nutrients are scarce due to limited blood flow and elevated tumour growth. Metabolic adaptation is required for breast cancer cells to endure these conditions. Here, we demonstrated that the presence of ECM supported the growth of invasive breast cancer cells, but not non-transformed mammary epithelial cells, under amino acid starvation, through a mechanism that required ECM uptake. Importantly, we showed that this behaviour was acquired during carcinoma progression. ECM internalisation, followed by lysosomal degradation, contributed to the upregulation of the intracellular levels of several amino acids, including tyrosine and phenylalanine. Finally, we showed that cells on ECM had elevated tyrosine catabolism, leading to elevated fumarate levels, potentially feeding into the tricarboxylic acid cycle. Interestingly, this pathway was required for ECM-dependent cell growth under amino acid starvation, as the knockdown of HPDL, the third enzyme of the pathway, opposed cell growth on ECM without affecting cell proliferation on plastic. Collectively, our results highlight that the ECM surrounding breast cancer tumours represents an alternative source of nutrients to support cancer cell growth, by regulating phenylalanine and tyrosine metabolism.

show abstract

Section: Discussionmentioning

confidence: 99%

The extracellular matrix supports cancer cell growth under amino acid starvation by promoting tyrosine catabolism

Nazemi

Yanes

Martinez

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…Li et al (32) revealed that FAM124B has a higher DNA methylation level in ER+/PR+ breast cancer compared with ER-/PR-breast cancers. HPDL is an iron-dependent dioxygenase involved in tyrosine catabolism (33). Ye et al (34) reported that HPDL promoted the proliferation of pancreatic cancer cells and was associated with glutamine-mediated redox balance.…”

Section: Discussionmentioning

confidence: 99%

New prognostic factors and scoring system for patients with acute myeloid leukemia

et al. 2021

View full text Add to dashboard Cite

Acute myeloid leukemia (AML) is a malignant disease originating from myeloid hematopoietic stem or progenitor cells. It is important to identify molecules associated with the prognosis of AML and conduct an individual risk assessment for different patients. In the present study, the RNA expression profile of 132 patients with AML and 337 healthy individuals were downloaded from the University of California Santa Cruz Xena and the Genotype-Tissue Expression project databases. Differentially expressed mRNA (DEmRNA) transcripts between normal blood and AML blood were identified. Among these, prognosis-associated signature mRNA molecules were screened using univariate Cox and least absolute shrinkage and selection operator regression. A total of four genes, namely, family with sequence similarity 124 member B (FAM124B), 4-hydroxyphenylpyruvate dioxygenase-like protein (HPDL), myeloperoxidase (MPO) and purinergic receptor P2Y1 (P2RY1), were identified using multivariate Cox regression analysis and were used to construct a prognostic scoring system. Moreover, the expression levels of HPDL and MPO were higher in the samples with high immunity scores and estimate scores (sum of stromal score and immune score), compared with those with low scores. Reverse transcription-quantitative PCR and western blot analysis were used to confirm the upregulation of the four candidate genes in AML cell lines as well as in clinical AML samples. In summary, the present study identified a novel mRNA-based prognostic risk scoring system for patients with AML. The four genes used in this scoring system may also play an important role in AML.

show abstract

“…However, lesions resembling LS emerged later. Previous reports also showed that HPDL variants cause pathology reminiscent of mitochondrial diseases, such as hyperlactatemia [3] , [4] , [5] , [6] . Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported [3] , [4] , [5] , [6] .…”

Section: Discussionmentioning

confidence: 93%

“…Previous reports also showed that HPDL variants cause pathology reminiscent of mitochondrial diseases, such as hyperlactatemia [3] , [4] , [5] , [6] . Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported [3] , [4] , [5] , [6] . Clinically, most HPDL -associated disorders with neonatal encephalopathy show diffuse white matter damage at the onset, as seen in this case, resulting in a severe phenotype [3] .…”

Section: Discussionmentioning

confidence: 93%

“…Over 75 disease-associated genes have been identified till date [2] . Recently, biallelic 4-hydroxyphenylpyruvate dioxygenase-like protein ( HPDL ) variants were reported as a cause of neurodegenerative diseases, which range from neonatal-onset mitochondrial leukoencephalopathy with severe neurodevelopmental delay to juvenile onset hereditary spastic paraplegia [3] , [4] , [5] , [6] . Neuroradiological findings associated with HPDL variants were also extremely diverse.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Leigh syndrome-like MRI changes in a patient with biallelic HPDL variants treated with ketogenic diet

Numata‐Uematsu

Uematsu

Yamamoto

et al. 2021

Molecular Genetics and Metabolism Reports

View full text Add to dashboard Cite

Biallelic 4-hydroxyphenylpyruvate dioxygenase-like protein ( HPDL ) variants were recently reported as a cause of progressive and incurable neurodegenerative diseases ranging from neonatal-onset leukoencephalopathy with severe neurodevelopmental delay to spastic paraplegia. Although the physiological function of HPDL remains unknown, its subcellular localization in the mitochondria has been reported. Here, we report a case of HPDL -related neurological disease that was clinically and neuroimaging compatible with Leigh syndrome, previously unreported, and was treated with a ketogenic diet.

show abstract

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

Cited by 20 publications

References 36 publications

The extracellular matrix supports cancer cell growth under amino acid starvation by promoting tyrosine catabolism

The extracellular matrix supports cancer cell growth under amino acid starvation by promoting tyrosine catabolism

New prognostic factors and scoring system for patients with acute myeloid leukemia

Leigh syndrome-like MRI changes in a patient with biallelic HPDL variants treated with ketogenic diet

Contact Info

Product

Resources

About