Encefalopatía epiléptica infantil precoz por mutación en ITPA

Alcón-Grases, M; Ferrer-Aliaga, N; Salinas-Salvador, B; Pérez-Delgado, R; Castejón-Ponce, E.; García-Jiménez, M.C.; Álvarez, Silvia Izquierdo; Pisón, J. López

doi:10.33588/rn.7105.2020239

Cited by 2 publications

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“…Genuine ITPA deficiency has been described for multiple patients and generally results in death at a young age [ 2 , 4 – 7 , 25 – 29 ]. Currently no treatment is available for this condition indicating a need to address this orphan disease.…”

Section: Discussionmentioning

confidence: 99%

“…ITPA polymorphism affects a substantial number of individuals [ 1 ] and can affect clinical outcomes [ 21 , 24 ] or result in severe developmental delays and infantile death [ 2 , 4 – 7 , 25 – 28 ]. To date, no therapies have been developed to address the clinical complications or treat this orphan disease.…”

Section: Discussionmentioning

confidence: 99%

“…To date, 45 patients have been reported to have very rare mutations which causes severe ITPA deficiency and high mortality in the first few years of life [ 2 , 4 – 7 , 25 – 29 ]. Several of the first patients identified were diagnosed with an early infantile condition termed developmental and epileptic encephalopathy 35 (DEE 35; MIM# 616,647) [ 2 , 27 ], while two later patients were diagnosed with a Martsolf-like syndrome with lethal infantile dilated cardiomyopathy [ 5 ].…”

Section: Introductionmentioning

confidence: 99%

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An ITPA Enzyme with Improved Substrate Selectivity

Burgis,

VanWormer,

Robbins

et al. 2023

Protein J

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Recent clinical data have identified infant patients with lethal ITPA deficiencies. ITPA is known to modulate ITP concentrations in cells and has a critical function in neural development which is not understood. Polymorphism of the ITPA gene affects outcomes for both ribavirin and thiopurine based therapies and nearly one third of the human population is thought to harbor ITPA polymorphism. In a previous site-directed mutagenesis alanine screen of the ITPA substrate selectivity pocket, we identified the ITPA mutant, E22A, as a gain-of function mutant with enhanced ITP hydrolysis activity. Here we report a rational enzyme engineering experiment to investigate the biochemical properties of position 22 ITPA mutants and find that the E22D ITPA has two- and four-fold improved substrate selectivity for ITP over the canonical purine triphosphates ATP and GTP, respectively, while maintaining biological activity. The novel E22D ITPA should be considered as a platform for further development of ITPA therapies.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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An ITPA Enzyme with Improved Substrate Selectivity

Burgis,

VanWormer,

Robbins

et al. 2023

Protein J

View full text Add to dashboard Cite

show abstract

“…Severe ITPase deficiency was first reported as a cause of recessive developmental and epileptic encephalopathy in seven individuals from four families in 2015 (Kevelam et al, 2015). With subsequent reports, a total of 45 affected individuals from 36 families are now described (Alcon‐Grases et al, 2020; Burgess et al, 2019; Garg et al, 2022; Handley et al, 2019; Kaur et al, 2019; Rochtus et al, 2020; Sakamoto et al, 2020; Scala et al, 2022; Sharma et al, 2022). A majority of the described affected individuals have homozygous pathogenic variants, though a number of reports include compound‐heterozygous individuals.…”

Section: Itpase Deficiency and Clinically Relevant Variants In Itpamentioning

confidence: 99%

“…Polymorphisms in ITPA leading to partial loss of function have been reported since the late 1960s as causing a mild condition with accumulation of ITP in erythrocytes (Vanderheiden, 1965). More recently, biallelic loss‐of‐function ITPA variants leading to severe or complete loss of ITPase activity have been reported to cause a fatal infantile neurodevelopmental disorder characterized by epilepsy, hypotonia, microcephaly, and often, dilated cardiomyopathy (Alcon‐Grases et al, 2020; Garg et al, 2022; Handley et al, 2019; Kaur et al, 2019; Kevelam et al, 2015; Muthusamy et al, 2021; Sakamoto et al, 2020; Scala et al, 2022; Sharma et al, 2022). These recent studies have added to the ongoing interest in better understanding the cellular roles of ITPase and in elucidating the mechanisms underlying pathogenesis in its absence.…”

Section: Introductionmentioning

confidence: 99%

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

2023

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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

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Encefalopatía epiléptica infantil precoz por mutación en ITPA

Cited by 2 publications

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An ITPA Enzyme with Improved Substrate Selectivity

An ITPA Enzyme with Improved Substrate Selectivity

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

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