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PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome

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Harvard

Pelet, A, Skopova, V, Steuerwald, U, Baresova, V, Zarhrate, M, Plaza, J-M, Hnizda, A, Krijt, M, Souckova, O, Wibrand, F, Andorsdóttir, G, Joensen, F, Sedlak, D, Bleyer, AJ, Kmoch, S, Lyonnet, S & Zikanova, M 2019, 'PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome' Human Molecular Genetics, bind 28, nr. 22, s. 3805-3814. https://doi.org/10.1093/hmg/ddz237

APA

Pelet, A., Skopova, V., Steuerwald, U., Baresova, V., Zarhrate, M., Plaza, J-M., ... Zikanova, M. (2019). PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. Human Molecular Genetics, 28(22), 3805-3814. https://doi.org/10.1093/hmg/ddz237

CBE

Pelet A, Skopova V, Steuerwald U, Baresova V, Zarhrate M, Plaza J-M, Hnizda A, Krijt M, Souckova O, Wibrand F, Andorsdóttir G, Joensen F, Sedlak D, Bleyer AJ, Kmoch S, Lyonnet S, Zikanova M. 2019. PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. Human Molecular Genetics. 28(22):3805-3814. https://doi.org/10.1093/hmg/ddz237

MLA

Vancouver

Author

Pelet, Anna ; Skopova, Vaclava ; Steuerwald, Ulrike ; Baresova, Veronika ; Zarhrate, Mohammed ; Plaza, Jean-Marc ; Hnizda, Ales ; Krijt, Matyas ; Souckova, Olga ; Wibrand, Flemming ; Andorsdóttir, Guðrið ; Joensen, Fróði ; Sedlak, David ; Bleyer, Anthony J ; Kmoch, Stanislav ; Lyonnet, Stanislas ; Zikanova, Marie. / PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. I: Human Molecular Genetics. 2019 ; Bind 28, Nr. 22. s. 3805-3814.

Bibtex

@article{e7106b209a2641d78031067dfdb0bcf2,
title = "PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome",
abstract = "We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10{\%} of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25{\%} of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.",
author = "Anna Pelet and Vaclava Skopova and Ulrike Steuerwald and Veronika Baresova and Mohammed Zarhrate and Jean-Marc Plaza and Ales Hnizda and Matyas Krijt and Olga Souckova and Flemming Wibrand and Gu{\dh}ri{\dh} Andorsd{\'o}ttir and Fr{\'o}{\dh}i Joensen and David Sedlak and Bleyer, {Anthony J} and Stanislav Kmoch and Stanislas Lyonnet and Marie Zikanova",
note = "{\circledC} The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.",
year = "2019",
month = "11",
day = "15",
doi = "10.1093/hmg/ddz237",
language = "English",
volume = "28",
pages = "3805--3814",
journal = "Human Molecular Genetics",
issn = "0964-6906",
publisher = "Oxford University Press",
number = "22",

}

RIS

TY - JOUR

T1 - PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome

AU - Pelet, Anna

AU - Skopova, Vaclava

AU - Steuerwald, Ulrike

AU - Baresova, Veronika

AU - Zarhrate, Mohammed

AU - Plaza, Jean-Marc

AU - Hnizda, Ales

AU - Krijt, Matyas

AU - Souckova, Olga

AU - Wibrand, Flemming

AU - Andorsdóttir, Guðrið

AU - Joensen, Fróði

AU - Sedlak, David

AU - Bleyer, Anthony J

AU - Kmoch, Stanislav

AU - Lyonnet, Stanislas

AU - Zikanova, Marie

N1 - © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

PY - 2019/11/15

Y1 - 2019/11/15

N2 - We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.

AB - We report for the first time an autosomal recessive inborn error of de novo purine synthesis (DNPS)-PAICS deficiency. We investigated two siblings from the Faroe Islands born with multiple malformations resulting in early neonatal death. Genetic analysis of affected individuals revealed a homozygous missense mutation in PAICS (c.158A>G; p.Lys53Arg) that affects the structure of the catalytic site of the bifunctional enzyme phosphoribosylaminoimidazole carboxylase (AIRC, EC 4.1.1.21)/phosphoribosylaminoimidazole succinocarboxamide synthetase (SAICARS, EC 6.3.2.6) (PAICS). The mutation reduced the catalytic activity of PAICS in heterozygous carrier and patient skin fibroblasts to approximately 50 and 10% of control levels, respectively. The catalytic activity of the corresponding recombinant enzyme protein carrying the mutation p.Lys53Arg expressed and purified from E. coli was reduced to approximately 25% of the wild-type enzyme. Similar to other two known DNPS defects-adenylosuccinate lyase deficiency and AICA-ribosiduria-the PAICS mutation prevented purinosome formation in the patient's skin fibroblasts, and this phenotype was corrected by transfection with the wild-type but not the mutated PAICS. Although aminoimidazole ribotide (AIR) and aminoimidazole riboside (AIr), the enzyme substrates that are predicted to accumulate in PAICS deficiency, were not detected in patient's fibroblasts, the cytotoxic effect of AIr on various cell lines was demonstrated. PAICS deficiency is a newly described disease that enhances our understanding of the DNPS pathway and should be considered in the diagnosis of families with recurrent spontaneous abortion or early neonatal death.

U2 - 10.1093/hmg/ddz237

DO - 10.1093/hmg/ddz237

M3 - Journal article

VL - 28

SP - 3805

EP - 3814

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 22

ER -

ID: 58279778