Protein instability and functional defects caused by mutations of dihydro-orotate dehydrogenase in Miller syndrome patients

Fang, Jingxian; Uchiumi, Takeshi; Yagi, Minoru; Matsumoto, Shimpei; Amamoto, Rie; Saito, Toshiro; Takazaki, Shinya; Kanki, Tomotake; Yamaza, Haruyoshi; Nonaka, Kenichi; Kang, Dongchon

doi:10.1042/bsr20120046

Cited by 28 publications

(17 citation statements)

References 22 publications

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“…Mandibulofacial dysostosis (OMIM610536) with microcephaly syndrome shares some overlapping features with Treacher Collins syndrome and has been associated with disruption of a spliceosomal GTPase [Lines et al, 2012; Luquetti et al, 2013]. Among several acrofacial dysostoses, causative mutations have recently been identified in an enzyme involved in pyrimidine biosynthesis in association with Miller syndrome (OMIM 263750) [Fang et al, 2012;], and in a component of the pre-mRNA spliceosomal complex, with respect to Nager syndrome (OMIM 154400) [Bernier et al, 2012]. Here we explore recent progress in understanding the etiology, pathogenesis and management of Treacher Collins, Nager and Miller syndromes and the potential for therapeutic prevention of facial dysostoses (Fig.…”

Section: Facial Dysostosismentioning

confidence: 99%

Facial dysostoses: Etiology, pathogenesis and management

Trainor¹,

Andrews²

2013

American J of Med Genetics Pt C

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Approximately 1% of all live births exhibit a minor or major congenital anomaly. Of these approximately one-third display craniofacial abnormalities which are a significant cause of infant mortality and dramatically affect national health care budgets. To date, more than 700 distinct craniofacial syndromes have been described and in this review, we discuss the etiology, pathogenesis and management of facial dysostoses with a particular emphasis on Treacher Collins, Nager and Miller syndromes. As we continue to develop and improve medical and surgical care for the management of individual conditions, it is essential at the same time to better characterize their etiology and pathogenesis. Here we describe recent advances in our understanding of the development of facial dysostosis with a view towards early in-utero identification and intervention which could minimize the manifestation of anomalies prior to birth. The ultimate management for any craniofacial anomaly however, would be prevention and we discuss this possibility in relation to facial dysostosis.

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Section: Facial Dysostosismentioning

confidence: 99%

Facial dysostoses: Etiology, pathogenesis and management

Trainor¹,

Andrews²

2013

American J of Med Genetics Pt C

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“…In total, 13 mutations from exon 2 to exon 9 in the DHODH gene have been reported in Miller syndrome [16,17]. Previously, we identified that the G202A and R346W mutations cause deficient protein stability, and the R135C mutation does not affect stability, but impairs the substrate-induced enzymatic activity, suggesting that impairment of DHODH activity is linked to the Miller syndrome phenotype [18]. …”

Section: Introductionmentioning

confidence: 99%

Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction

et al. 2013

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Some mutations of the DHODH (dihydro-orotate dehydrogenase) gene lead to postaxial acrofacial dysostosis or Miller syndrome. Only DHODH is localized at mitochondria among enzymes of the de novo pyrimidine biosynthesis pathway. Since the pyrimidine biosynthesis pathway is coupled to the mitochondrial RC (respiratory chain) via DHODH, impairment of DHODH should affect the RC function. To investigate this, we used siRNA (small interfering RNA)-mediated knockdown and observed that DHODH knockdown induced cell growth retardation because of G2/M cell-cycle arrest, whereas pyrimidine deficiency usually causes G1/S arrest. Inconsistent with this, the cell retardation was not rescued by exogenous uridine, which should bypass the DHODH reaction for pyrimidine synthesis. DHODH depletion partially inhibited the RC complex III, decreased the mitochondrial membrane potential, and increased the generation of ROS (reactive oxygen species). We observed that DHODH physically interacts with respiratory complexes II and III by IP (immunoprecipitation) and BN (blue native)/SDS/PAGE analysis. Considering that pyrimidine deficiency alone does not induce craniofacial dysmorphism, the DHODH mutations may contribute to the Miller syndrome in part through somehow altered mitochondrial function.

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“…Recent studies on mammalian DHODH have shown that DHODH is physically associated with the respiratory chain complexes III and II (42). Moreover, depletion of DHODH induced cell cycle arrest and mitochondrial dysfunction (42)(43)(44). Here, we show that wild-type and mutant TgDHODH enzymes localized to the parasite mitochondria and that T. gondii expressing catalytically deficient DHODH retained an intact mitochondrial membrane potential even with reduced expression levels of catalytically deficient TgDHODH enzymes.…”

Section: Discussionmentioning

confidence: 69%

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase

et al. 2016

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bDihydroorotate dehydrogenase (DHODH) mediates the fourth step of de novo pyrimidine biosynthesis and is a proven drug target for inducing immunosuppression in therapy of human disease as well as a rapidly emerging drug target for treatment of malaria. In Toxoplasma gondii, disruption of the first, fifth, or sixth step of de novo pyrimidine biosynthesis induced uracil auxotrophy. However, previous attempts to generate uracil auxotrophy by genetically deleting the mitochondrion-associated DHODH of T. gondii (TgDHODH) failed. To further address the essentiality of TgDHODH, mutant gene alleles deficient in TgDHODH activity were designed to ablate the enzyme activity. Replacement of the endogenous DHODH gene with catalytically deficient DHODH gene alleles induced uracil auxotrophy. Catalytically deficient TgDHODH localized to the mitochondria, and parasites retained mitochondrial membrane potential. These results show that TgDHODH is essential for the synthesis of pyrimidines and suggest that TgDHODH is required for a second essential function independent of its role in pyrimidine biosynthesis.

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Protein instability and functional defects caused by mutations of dihydro-orotate dehydrogenase in Miller syndrome patients

Cited by 28 publications

References 22 publications

Facial dysostoses: Etiology, pathogenesis and management

Facial dysostoses: Etiology, pathogenesis and management

Dihydro-orotate dehydrogenase is physically associated with the respiratory complex and its loss leads to mitochondrial dysfunction

Pyrimidine Pathway-Dependent and -Independent Functions of the Toxoplasma gondii Mitochondrial Dihydroorotate Dehydrogenase

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