Protein-lipid interactions of human dihydroorotate dehydrogenase and three mutants associated with Miller syndrome

Rodriguez, Juan Manuel Orozco; Wacklin-Knecht, Hanna; Knecht, Wolfgang

doi:10.1080/15257770.2022.2039393

Cited by 2 publications

(4 citation statements)

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“…The extremely low incidence and mutation amount of DHODH ‐caused Miller syndrome, one recessive type of AFD, adds a layer of mystery to its pathogenesis (Duley et al, 2016 ). There has been even less in‐depth research into the effects of specific mutations of DHODH gene (Orozco Rodriguez et al, 2022 ).…”

Section: Discussionmentioning

confidence: 99%

“…DHODH is located at chromosome 16q22.2 and contains nine exons encoding dihydroorotate dehydrogenase, which catalyzes the fourth step in de novo pyrimidine biosynthesis (Minet et al, 1992 ). To date, only 21 DHODH variants in nine studies have been reported to cause Miller syndrome ( https://www.hgmd.cf.ac.uk/ ; pro V2021.10; details see Table 1 ), demonstrating a low incidence of this condition and a strong conservatism of DHODH gene (Bukowska‐Olech et al, 2020 ; Duley et al, 2016 ; Fujikura, 2016 ; Hou et al, 2020 ; Kinoshita et al, 2011 ; Ng et al, 2010 ; Orozco Rodriguez et al, 2022 ; Rainger et al, 2012 ; Roach et al, 2010 ); in them, missense variants accounted for the most part (~69.6%, Table 1 ), and the others were base‐level deletion, duplication or frameshift variants. The subjects of previous studies were limited to Caucasian and Japanese populations, and there are no reports on other ethnic groups.…”

Section: Introductionmentioning

confidence: 99%

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Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population

Yang

Chu

et al. 2023

Molec Gen & Gen Med

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Background Miller syndrome is a rare type of postaxial acrofacial dysostosis caused by biallelic mutations in the DHODH gene, which is characterized mainly by craniofacial malformations of micrognathia, orofacial clefts, cup‐shaped ears, and malar hypoplasia, combined with postaxial limb deformities like the absence of fifth digits. Methods In this study, a prenatal case with multiple orofacial‐limb abnormities was enrolled, and a thorough clinical and imaging examination was performed. Subsequently, genetic detection with karyotyping, chromosomal microarray analysis (CMA) and whole‐exome sequencing (WES) was carried out. In vitro splicing analysis was also conducted to clarify the impact of one novel variant. Results The affected fetus displayed typical manifestations of Miller syndrome, and WES identified a diagnostic compound heterozygous variation in DHODH, consisting of two variants: exon(1‐3)del and c.819 + 5G > A. We conducted a further in vitro validation with minigene system, and the result indicated that the c.819 + 5G > A variant would lead to an exon skipping in mRNA splicing. Conclusions These findings provided with the first exonic deletion and first splice site variant in DHODH, which expanded the mutation spectrum of Miller syndrome and offered reliable evidence for genetic counseling to the affected family.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population

Yang

Chu

et al. 2023

Molec Gen & Gen Med

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Section: Targeting Glucose Metabolismmentioning

confidence: 99%

“…In addition, melatonin increases oxidative phosphorylation (OXPHOS) in HNSCC and inhibits glycolysis, resulting in increased reactive oxygen species production, apoptosis and mitotic phagocytosis, and reduced cell proliferation (Guerra‐Librero et al, 2021). Mitochondrial inner membrane protein dihydroorotate dehydrogenase (DHODH), which is usually upregulated in HNSCC, is a rate‐limiting step to control de novo pyrimidine synthesis by catalyzing the conversion of dihydroorotate to orotate through an oxidation reaction (Löffler et al, 2020; Orozco Rodriguez et al, 2022). BAY 2402234 and Vidofludimus are selective and powerful DHODH antagonists that can damage the synthesis of pyrimidine nucleotides and destroy the stability of the mitochondrial contact site and cristae tissue system (MICOS) complex, thus destroying mitochondrial homeostasis (Christian et al, 2019; Muehler et al, 2020; Qiu et al, 2021; shown in Figure 2).…”

Section: Targeting Specific Metabolic Pathways In Hnsccmentioning

confidence: 99%

Targeting cellular metabolism in head and neck cancer precision medicine era: A promising strategy to overcome therapy resistance

et al. 2022

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Head and neck squamous cell carcinoma (HNSCC) is among the most prevalent cancer worldwide, with the most severe impact on quality of life of patients. Despite the development of multimodal therapeutic approaches, the clinical outcomes of HNSCC are still unsatisfactory, mainly caused by relatively low responsiveness to treatment and severe drug resistance. Metabolic reprogramming is currently considered to play a pivotal role in anticancer therapeutic resistance. This review aimed to define the specific metabolic programs and adaptations in HNSCC therapy resistance. An extensive literature review of HNSCC was conducted via the PubMed including metabolic reprogramming, chemo‐ or immune‐therapy resistance. Glucose metabolism, fatty acid metabolism, and amino acid metabolism are closely related to the malignant biological characteristics of cancer, anti‐tumor drug resistance, and adverse clinical results. For HNSCC, pyruvate, lactate and almost all lipid categories are related to the occurrence and maintenance of drug resistance, and targeting amino acid metabolism can prevent tumor development and enhance the response of drug‐resistant tumors to anticancer therapy. This review will provide a better understanding of the altered metabolism in therapy resistance of HNSCC and promote the development of new therapeutic strategies against HNSCC, thereby contribute to a more efficacious precision medicine.

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Protein-lipid interactions of human dihydroorotate dehydrogenase and three mutants associated with Miller syndrome

Cited by 2 publications

References 23 publications

Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population

Assessment of a novel variation in DHODH gene causing Miller syndrome: The first report in Chinese population

Targeting cellular metabolism in head and neck cancer precision medicine era: A promising strategy to overcome therapy resistance

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