Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

Koga, Yuichiro; Tsuchimoto, Daisuke; Hayashi, Yoshinori; Abolhassani, Nona; Yoneshima, Yasuto; Sakumi, Kunihiko; Nakanishi, Hiroshi; Toyokuni, Shinya; Nakabeppu, Yusaku

doi:10.1172/jci.insight.140229

Cited by 7 publications

(5 citation statements)

References 61 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In such cases, it is observed that Arg-178 is replaced with cysteine [11,21]. Moreover, a study also showed that ITPase deficiency may lead to refractory epilepsy, microcephaly, and neurodevelopmental disease [22]. The effect of ITPase deficiency on neural epilepsy has been confirmed in knockout mice [23], which is also supported by another mice study that showed ITPase deficiency may lead to growth retardation [24].…”

Section: Infantile Encephalopathymentioning

confidence: 79%

“…In view of the ongoing evidence finding that the phenotypic series of ITPA defects ranges from very mild to severe deaths, it was also suggested that therapies will be developed to regulate ITPase activity. The ITPA status contributes to several severe diseases, from cardiomyopathy to neural defects and disorders of the immune system, as well as several other ITPA-related diseases [4,22,23]. The low-cost development of sequencing techniques, such as NGS and WES, will help to evaluate several other ITPase-related diseases.…”

Section: Final Remarksmentioning

confidence: 99%

See 1 more Smart Citation

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Zamzami

2022

Cells

View full text Add to dashboard Cite

Inosine triphosphate pyrophosphatase (ITPase) is an enzyme encoded by the ITPA gene and functions to prevent the incorporation of noncanonical purine nucleotides into DNA and RNA. Specifically, the ITPase catalyzed the hydrolysis of (deoxy) nucleoside triphosphates ((d) NTPs) into the corresponding nucleoside monophosphate with the concomitant release of pyrophosphate. Recently, thiopurine drug metabolites such as azathioprine have been included in the lists of ITPase substrates. Interestingly, inosine or xanthosine triphosphate (ITP/XTP) and their deoxy analogs, deoxy inosine or xanthosine triphosphate (dITP/dXTP), are products of important biological reactions such as deamination that take place within the cellular compartments. However, the incorporation of ITP/XTP, dITP/dXTP, or the genetic deficiency or polymorphism of the ITPA gene have been implicated in many human diseases, including infantile epileptic encephalopathy, early onset of tuberculosis, and the responsiveness of patients to cancer therapy. This review provides an up-to-date report on the ITPase enzyme, including information regarding its discovery, analysis, and cellular localization, its implication in human diseases including cancer, and its therapeutic potential, amongst others.

show abstract

Section: Infantile Encephalopathymentioning

confidence: 79%

Section: Final Remarksmentioning

confidence: 99%

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Zamzami

2022

Cells

View full text Add to dashboard Cite

show abstract

“…In addition, these mice show impaired growth and abnormal heart morphology and function that likely contributes to their reduced survival (Behmanesh et al, 2009). Subsequent characterization of neural‐cell‐specific conditional ITPase‐null mice generated with Nestin‐Cre has established that these animals die between p18 and p22 without embryonic lethality (Koga et al, 2020). Neurons from the conditional‐null animals show altered electrophysiological properties indicative of increased neuronal activity, the animals show spontaneous and audiogenic seizures, and they display hindlimb clasping indicative of neurological dysfunction (Koga et al, 2020).…”

Section: Itpase Deficiency and Clinically Relevant Variants In Itpamentioning

confidence: 99%

“…Subsequent characterization of neural‐cell‐specific conditional ITPase‐null mice generated with Nestin‐Cre has established that these animals die between p18 and p22 without embryonic lethality (Koga et al, 2020). Neurons from the conditional‐null animals show altered electrophysiological properties indicative of increased neuronal activity, the animals show spontaneous and audiogenic seizures, and they display hindlimb clasping indicative of neurological dysfunction (Koga et al, 2020). There are differences in the literature regarding the extent of dITP‐misincorporation into DNA in ITPase‐null mouse models and its effects (Abolhassani et al, 2010; Handley et al, 2019).…”

Section: Itpase Deficiency and Clinically Relevant Variants In Itpamentioning

confidence: 99%

Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function

2023

View full text Add to dashboard Cite

Inosine triphosphate pyrophosphatase (ITPase), encoded by the ITPA gene in humans, is an important enzyme that preserves the integrity of cellular nucleotide pools by hydrolyzing the noncanonical purine nucleotides (deoxy)inosine and (deoxy)xanthosine triphosphate into monophosphates and pyrophosphate. Variants in the ITPA gene can cause partial or complete ITPase deficiency. Partial ITPase deficiency is benign but clinically relevant as it is linked to altered drug responses. Complete ITPase deficiency causes a severe multisystem disorder characterized by seizures and encephalopathy that is frequently associated with fatal infantile dilated cardiomyopathy. In the absence of ITPase activity, its substrate noncanonical nucleotides have the potential to accumulate and become aberrantly incorporated into DNA and RNA. Hence, the pathophysiology of ITPase deficiency could arise from metabolic imbalance, altered DNA or RNA regulation, or from a combination of these factors. Here, we review the known functions of ITPase and highlight recent work aimed at determining the molecular basis for ITPA‐associated pathogenesis which provides evidence for RNA dysfunction.This article is categorized under: RNA in Disease and Development > RNA in Disease RNA in Disease and Development > RNA in Development

show abstract

“…The triphosphate forms of canonical and non-canonical nucleotides are removed by inosine triphosphate pyrophosphatase (ITPase), which is encoded by the ITPA gene ( 32 ), and the genetic defects in ITPA gene is closely related to various human diseases such as early infantile encephalopathy ( 33 ), infantile dilated cardiomyopathy ( 34 ) and neural depolarization and epilepsy ( 35 ). Ham1p, a yeast homolog of ITPase, was reported to remove the triphosphate form of non-canonical pyrimidines including 5-FU and the overexpression of Ham1p may contribute to the 5-FU resistance ( 36 , 37 ).…”

Section: Introductionmentioning

confidence: 99%

Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer

Averill,

Lin,

Jung

et al. 2024

Nucleic Acids Research

View full text Add to dashboard Cite

5-Fluorouracil (5-FU) is the first-line chemotherapeutic agent in colorectal cancer, and resistance to 5-FU easily emerges. One of the mechanisms of drug action and resistance of 5-FU is through DNA incorporation. Our quantitative reverse-transcription PCR data showed that one of the translesion synthesis (TLS) DNA polymerases, DNA polymerase η (polη), was upregulated within 72 h upon 5-FU administration at 1 and 10 μM, indicating that polη is one of the first responding polymerases, and the only TLS polymerase, upon the 5-FU treatment to incorporate 5-FU into DNA. Our kinetic studies revealed that 5-fluoro-2′-deoxyuridine triphosphate (5FdUTP) was incorporated across dA 41 and 28 times more efficiently than across dG and across inosine, respectively, by polη indicating that the mutagenicity of 5-FU incorporation is higher in the presence of inosine and that DNA lesions could lead to more mutagenic incorporation of 5-FU. Our polη crystal structures complexed with DNA and 5FdUTP revealed that dA:5FdUTP base pair is like dA:dTTP in the active site of polη, while 5FdUTP adopted 4-enol tautomer in the base pairs with dG and HX increasing the insertion efficiency compared to dG:dTTP for the incorrect insertions. These studies confirm that polη engages in the DNA incorporation and bypass of 5-FU.

show abstract

Neural stem cell–specific ITPA deficiency causes neural depolarization and epilepsy

Cited by 7 publications

References 61 publications

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Inosine Triphosphate Pyrophosphatase (ITPase): Functions, Mutations, Polymorphisms and Its Impact on Cancer Therapies

Inosine triphosphate pyrophosphatase: A guardian of the cellular nucleotide pool and potential mediator of RNA function

Novel insights into the role of translesion synthesis polymerase in DNA incorporation and bypass of 5-fluorouracil in colorectal cancer

Contact Info

Product

Resources

About