Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband

Watkins, David; Schwartzentruber, Jeremy; Ganesh, Jaya; Orange, Jordan S.; Kaplan, Bernard S.; Nunez, Laura Dempsey; Majewski, Jacek; Rosenblatt, David S.

doi:10.1136/jmedgenet-2011-100286

Cited by 68 publications

(44 citation statements)

References 12 publications

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“…Human mutations in MTHFD1 cause severe combined immunodeficiency and megaloblastic anemia as a result of disrupted dTMP biosynthesis (18,31,32). Human MTHFD1 polymorphisms are associated with increased risk for NTDs, as well as congenital heart defects (33,34).…”

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confidence: 99%

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Arsenic exposure increases risk for cancers and is teratogenic in animal models. Here we demonstrate that small ubiquitin-like modifier (SUMO)-and folate-dependent nuclear de novo thymidylate (dTMP) biosynthesis is a sensitive target of arsenic trioxide (As 2 O 3 ), leading to uracil misincorporation into DNA and genome instability. Methylenetetrahydrofolate dehydrogenase 1 (MTHFD1) and serine hydroxymethyltransferase (SHMT) generate 5,10-methylenetetrahydrofolate for de novo dTMP biosynthesis and translocate to the nucleus during S-phase, where they form a multienzyme complex with thymidylate synthase (TYMS) and dihydrofolate reductase (DHFR), as well as the components of the DNA replication machinery. As 2 O 3 exposure increased MTHFD1 SUMOylation in cultured cells and in in vitro SUMOylation reactions, and increased MTHFD1 ubiquitination and MTHFD1 and SHMT1 degradation. As 2 O 3 inhibited de novo dTMP biosynthesis in a dose-dependent manner, increased uracil levels in nuclear DNA, and increased genome instability. These results demonstrate that MTHFD1 and SHMT1, which are key enzymes providing one-carbon units for dTMP biosynthesis in the form of 5,10-methylenetetrahydrofolate, are direct targets of As 2 O 3 -induced proteolytic degradation, providing a mechanism for arsenic in the etiology of cancer and developmental anomalies.MTHFD1 | arsenic trioxide | one-carbon metabolism | SUMO-1

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confidence: 99%

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Kamynina

Lachenauer

DiRisio

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…Successful identification of the Schinzel-Gideon syndrome allele underscores the idea that, while "Protein coding genes constitute only approximately 1% of the human genome but harbor 85% of the mutations" [46], they need not remain unidentified. Developmental delay -related genetic targets such as non-syndromic mental retardation [47], mental retardation [32] and sporadic autism spectrum disorders characterize novel candidates for identification by whole exome sequencing, even when complicated by consanguinity [48] and de novo occurrences [49].…”

Section: Genetic Targets Related To Developmental Delaymentioning

confidence: 99%

Neurological disorders, genetic correlations, and the role of exome sequencing

Brown¹,

Meloche²

2016

J Transl Sci

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Genomic information access and utilization by researchers and clinicians have barely begun the journey for fulfillment of their full potential in the research and clinical arenas. Exciting is the potential depth and breadth of research, clinical applications, and more personalized medicine, that remain on the horizon. Exome sequencing has clarified the responsibilities of over 130 genes, greatly expanding the medical genetics database and enabling the development of orphan diseasebased pharmaceuticals. The focus of our research efforts was to review several literature sources related to rare genomic disease research and exome sequencing, as well as to review the new research and diagnostic strategies that were utilized. Using a systems approach, under discussion are neurology, neuropathy, and the central nervous and musculoskeletal systems. Also discussed will be the topics of inborn errors of metabolism, and the genetic targets related to developmental delay. Recommendations for future research will also be discussed. Exome sequencing A review of new strategies for rare genomic disease researchThis literature review will examine several publications in which the authors demonstrate the success of whole exome sequencing (WES) in circumstances where traditional methods have presented ambiguous interpretations or failed altogether, for instance, single -subject populations, large candidate counts and reduced reproductive fitness [1]. By supporting exome sequencing, we will show that there is an increasing need for polymorphism databases and assay strategies that do not depend on positional information, if genomic medicine is to advance its research and clinical utility. Within our review, we will discuss the research related to neurology, neuropathy, the central nervous system, the musculoskeletal system, inborn errors of metabolism, and the genetic targets related to developmental delay. Recommendations for future research will also be discussed. Disease survey NeurologyPositional cloning techniques have thus far unveiled 19 contributory genes in the study of 31 genetic variations of autosomal dominant spinocerebellar ataxia [2]. The method has yet to overcome the challenges that presented, such as phenotypic and biological manifestations which do not correlate well to molecular mutations due to the exceedingly complex nature of the brain. Exome sequencing has, however, shed additional light on causal mutations for sensory motor neuropathy with ataxia [3], which presents with cerebellar dysfunction, Spinocerebellar Ataxia with Psychomotor Retardation [4], and Spastic Ataxia-Neuropathy syndrome that manifested with remarkable variety between two brothers [5] due to different mutations in the same protease subunits.A United States incidence of 1 in 12,500 live births makes neuronal ceroid lipofuscinoses the most common group of inherited neurological degenerative disorders [6]. Whether examining the mitochondrial defect implicated in prenatal ventriculomegaly [7], the often early-stage atypical presentation...

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“…The NGS technology has been used to discover many novel genes that cause mitochondrial related disorders on research bases [1,[9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24][25][26][27]. It is now time to bring this technology to clinical diagnosis.…”

Section: Introductionmentioning

confidence: 99%

Challenges of Bringing Next Generation Sequencing Technologies to Clinical Molecular Diagnostic Laboratories

Wong

2013

Neurotherapeutics

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Molecular diagnosis of complex dual genome mitochondrial disorders is a challenge. It requires the identification of deleterious mutations in one of the~1,500 nuclear genes and the mitochondrial genome. If the molecular defect is in the mitochondrial genome, quantification of degree of mutation load (heteroplasmy) in affected tissues is important. Due to the extreme clinical and genetic heterogeneity, conventional sequence analysis of the candidate genes one-byone is impractical, if not impossible. The newly developed massively parallel next generation sequencing (NGS) technique, that allows simultaneous sequence analysis of multiple target genes, when appropriately validated with deep coverage and proper quality controls, can be used as an effective comprehensive diagnostic approach in CLIA certified clinical laboratories.

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Novel inborn error of folate metabolism: identification by exome capture and sequencing of mutations in the MTHFD1 gene in a single proband

Abstract: This patient represents the first case of an inborn error of folate metabolism affecting the trifunctional MTHFD1 protein. This report reinforces the power of exome capture and sequencing for the discovery of novel genes, even when only a single proband is available for study.

Cited by 68 publications

References 12 publications

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Arsenic trioxide targets MTHFD1 and SUMO-dependent nuclear de novo thymidylate biosynthesis

Neurological disorders, genetic correlations, and the role of exome sequencing

Challenges of Bringing Next Generation Sequencing Technologies to Clinical Molecular Diagnostic Laboratories

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