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

Result code in IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F68378050%3A_____%2F19%3A00522814" target="_blank" >RIV/68378050:_____/19:00522814 - isvavai.cz</a>

Alternative codes found

RIV/00216208:11110/19:10404241 RIV/00064165:_____/19:10404241

Result on the web

<a href="https://academic.oup.com/hmg/article/28/22/3805/5584440" target="_blank" >https://academic.oup.com/hmg/article/28/22/3805/5584440</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/hmg/ddz237" target="_blank" >10.1093/hmg/ddz237</a>

Result language

angličtina

Original language name

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

Original language description

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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

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OECD FORD branch

10603 - Genetics and heredity (medical genetics to be 3)

Project

Result was created during the realization of more than one project. More information in the Projects tab.

Continuities

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Publication year

2019

Confidentiality

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Name of the periodical

Human Molecular Genetics

ISSN

0964-6906

e-ISSN

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Volume of the periodical

28

Issue of the periodical within the volume

22

Country of publishing house

GB - UNITED KINGDOM

Number of pages

10

Pages from-to

3805-3814

UT code for WoS article

000506824300010

EID of the result in the Scopus database

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