Novel cases of D-2-hydroxyglutaric aciduria with<i>IDH1</i>or<i>IDH2</i>mosaic mutations identified by amplicon deep sequencing

Nota, Benjamin; Hamilton, Eline M.; Sie, Daoud; Öztürk, Şenay; Dooren, Silvy J.M. van; Ojeda, Matilde R. Fernandez; Jakobs, Cornelis; Christensen, Ernst; Kirk, Edwin P.; Sykut-Cegielska, Jolanta; Lund, Allan M.; Knaap, Marjo S. van der; Salomons, Gajja S.

doi:10.1136/jmedgenet-2013-101961

Cited by 18 publications

(17 citation statements)

References 26 publications

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“…78,79 We developed this Drosophila model to enable rapid in vivo assays to identify genetic interactions with mutant IDH, in order to map the molecular pathways by which mutant IDH exerts biological phenotypes and to discover therapeutic susceptibilities of IDHmutated cancer tissues. We used this system to test whether a focused panel of candidate genes interacted with mutant IDH in the fly.…”

Section: Discussionmentioning

confidence: 99%

“…77 Germline IDH1-R132H mutation has been speculated to be incompatible with human development because it has only been observed in a mosaic distribution, and even then it is associated with severe metaphysical chondromatosis and D-2-hydroxyglutaric aciduria. 78,79 We developed this Drosophila model to enable rapid in vivo assays to identify genetic interactions with mutant IDH, in order to map the molecular pathways by which mutant IDH exerts biological phenotypes and to discover therapeutic susceptibilities of IDHmutated cancer tissues. We used this system to test whether a focused panel of candidate genes interacted with mutant IDH in the fly.…”

Section: Discussionmentioning

confidence: 99%

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Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Reitman

Sinenko

Spana

et al. 2015

Blood

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Key Points• Homologs to cancer-derived IDH1 and IDH2 mutants produce D-2HG and drive expansion of Drosophila blood cells. • In flies, mutant Idh interactswith genes that regulate reduced nicotinamide adenine dinucleotide phosphate, reactive oxygen species, and apoptosis.Gain-of-function mutations in nicotinamide adenine dinucleotide phosphate-dependent isocitrate dehydrogenase (IDH)1 and IDH2 frequently arise in human leukemias and other cancers and produce high levels of D-2-hydroxyglutarate (D-2HG). We expressed the R195H mutant of Drosophila Idh (CG7176), which is equivalent to the human cancerassociated IDH1-R132H mutant, in fly tissues using the UAS-Gal4 binary expression system. Idh-R195H caused a >25-fold elevation of D-2HG when expressed ubiquitously in flies. Expression of mutant Idh in larval blood cells (hemocytes) resulted in higher numbers of circulating blood cells. Mutant Idh expression in fly neurons resulted in neurologic and wing-expansion defects, and these phenotypes were rescued by genetic modulation of superoxide dismutase 2, p53, and apoptotic caspase cascade mediators. Idh-R163Q, which is homologous to the common leukemia-associated IDH2-R140Q mutant, resulted in moderately elevated D-2HG and milder phenotypes. We identified the fly homolog of D-2-hydroxyglutaric acid dehydrogenase (CG3835), which metabolizes D-2HG, and showed that coexpression of this enzyme with mutant Idh abolishes mutant Idh-associated phenotypes. These results provide a flexible model system to interrogate a cancer-related genetic and metabolic pathway and offer insights into the impact of IDH mutation and D-2HG on metazoan tissues. (Blood. 2015;125(2):336-345) Introduction Somatic, gain-of-function mutations in nicotinamide adenine dinucleotide phosphate (NADP 1 )-dependent isocitrate dehydrogenase (IDH)1 and IDH2 occur frequently in acute myeloid leukemias, myelodysplastic syndromes, angioimmunoblastic T-cell lymphomas, brain tumors, and other cancers. [1][2][3][4][5][6][7][8][9] The mutations occur at the conserved active-site residues of Arg132 in IDH1, or Arg140 and Arg172 in IDH2. When mutated, IDH1 and IDH2 lose their normal function to convert isocitrate to a-ketoglutarate and acquire a gain of function to convert a-ketoglutarate to D-2-hydroxyglutarate (D-2HG).10 D-2HG accumulates to ;100-fold higher levels in IDHmutated cancer tissues.10,11 D-2HG inhibits Fe(II)-a-ketoglutaratedependent dioxygenases, including histone demethylases, DNA hydroxymethyltransferases, and collagen proline hydroxylases. 12,13 Inhibition of these dioxygenase enzymes leads to histone lysine hypermethylation, DNA hypermethylation, and collagen dysfunction in mammalian tissues expressing mutated IDH1 or IDH2. 5,[14][15][16] IDH mutations can also sensitize cells to reactive oxygen species (ROS) induction, possibly because mutant IDH consumes reduced NADP (NADPH), a cofactor important for scavenging intracellular ROS. 17 Targeting mutated IDH1 or IDH2 to mouse hematopoietic progenitors results in an increased number of these progeni...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Reitman

Sinenko

Spana

et al. 2015

Blood

View full text Add to dashboard Cite

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“…These technologies include pyrosequencing [White et al., ], allele‐specific quantitative PCR such as mismatch amplification mutation assay and high‐resolution melting curve [Wittwer et al., ], TaqMAMA [Depienne et al., ]), digital PCR [Chen et al., ; Campbell et al., ], denaturing HPLC (DHPLC) [Jones et al., ], mass spectrometry [Lee et al., ], restricted fragment length polymorphism [Selmer et al., ], single‐strand conformation polymorphism/heteroduplex analysis [Orita et al., ], and the protein truncation test [Rohlin et al., ]. Recently, next‐generation sequencing (NGS) technologies have been used to identify mosaicism [Rohlin et al., ] in cancer and 14 non‐cancer diseases such as d ‐2‐hydroxyglutaric aciduria [Nota et al., ], Alport syndrome [Artuso et al., ], and TSC [Qin et al., ]. Compared to other mosaic detection technologies, NGS‐based methods have the advantage of being quantitative and having higher throughput.…”

Section: Introductionmentioning

confidence: 99%

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “ de novo ” SCN1A Mutations in Children with Dravet Syndrome

et al. 2015

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The majority of children with Dravet syndrome (DS) are caused by de novo SCN1A mutations. To investigate the origin of the mutations, we developed and applied a new method that combined deep amplicon resequencing with a Bayesian model to detect and quantify allelic fractions with improved sensitivity. Of 174 SCN1A mutations in DS probands which were considered “de novo” by Sanger sequencing, we identified 15 cases (8.6%) of parental mosaicism. We identified another five cases of parental mosaicism that were also detectable by Sanger sequencing. Fraction of mutant alleles in the 20 cases of parental mosaicism ranged from 1.1% to 32.6%. Thirteen (65% of 20) mutations originated paternally and seven (35% of 20) maternally. Twelve (60% of 20) mosaic parents did not have any epileptic symptoms. Their mutant allelic fractions were significantly lower than those in mosaic parents with epileptic symptoms (P = 0.016). We identified mosaicism with varied allelic fractions in blood, saliva, urine, hair follicle, oral epithelium, and semen, demonstrating that postzygotic mutations could affect multiple somatic cells as well as germ cells. Our results suggest that more sensitive tools for detecting low‐level mosaicism in parents of families with seemingly “de novo” mutations will allow for better informed genetic counseling.

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“…Emerging evidence has demonstrated the previously neglected contribution of postzygotic mutations in the etiology of non-cancer diseases (53–56). Within a healthy individual, postzygotic mutations identified in different samples of the same individual have broadened the concept of ‘a personal genome’ to ‘the personal genomes’ (2,4,6).…”

Section: Discussionmentioning

confidence: 99%

MosaicHunter: accurate detection of postzygotic single-nucleotide mosaicism through next-generation sequencing of unpaired, trio, and paired samples

Huang

Zhang

et al. 2017

Nucleic Acids Research

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Genomic mosaicism arising from postzygotic mutations has long been associated with cancer and more recently with non-cancer diseases. It has also been detected in healthy individuals including healthy parents of children affected with genetic disorders, highlighting its critical role in the origin of genetic mutations. However, most existing software for the genome-wide identification of single-nucleotide mosaicisms (SNMs) requires a paired control tissue obtained from the same individual which is often unavailable for non-cancer individuals and sometimes missing in cancer studies. Here, we present MosaicHunter (http://mosaichunter.cbi.pku.edu.cn), a bioinformatics tool that can identify SNMs in whole-genome and whole-exome sequencing data of unpaired samples without matched controls using Bayesian genotypers. We evaluate the accuracy of MosaicHunter on both simulated and real data and demonstrate that it has improved performance compared with other somatic mutation callers. We further demonstrate that incorporating sequencing data of the parents can be an effective approach to significantly improve the accuracy of detecting SNMs in an individual when a matched control sample is unavailable. Finally, MosaicHunter also has a paired mode that can take advantage of matched control samples when available, making it a useful tool for detecting SNMs in both non-cancer and cancer studies.

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Novel cases of D-2-hydroxyglutaric aciduria withIDH1orIDH2mosaic mutations identified by amplicon deep sequencing

Cited by 18 publications

References 26 publications

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Genetic dissection of leukemia-associated IDH1 and IDH2 mutants and D-2-hydroxyglutarate in Drosophila

Amplicon Resequencing Identified Parental Mosaicism for Approximately 10% of “ de novo ” SCN1A Mutations in Children with Dravet Syndrome

MosaicHunter: accurate detection of postzygotic single-nucleotide mosaicism through next-generation sequencing of unpaired, trio, and paired samples

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