Research
Print page Print page
Switch language
The Capital Region of Denmark - a part of Copenhagen University Hospital
Published

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

Research output: Contribution to journalJournal articleResearchpeer-review

DOI

  1. The Duffy-null genotype and risk of infection

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Functional Assessment of Variants Associated with Wolfram Syndrome

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. A Trans-ancestral Meta-Analysis of Genome-Wide Association Studies Reveals Loci Associated with Childhood Obesity

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Consortium-based genome-wide meta-analysis for childhood dental caries traits

    Research output: Contribution to journalJournal articleResearchpeer-review

  5. Mutations involving the SRY-related gene SOX8 are associated with a spectrum of human reproductive anomalies

    Research output: Contribution to journalJournal articleResearchpeer-review

  1. Increased antioxidant response in medium-chain acyl-CoA dehydrogenase deficiency: does lipoic acid have a protective role?

    Research output: Contribution to journalJournal articleResearchpeer-review

  2. Danish expanded newborn screening is a successful preventive public health programme

    Research output: Contribution to journalJournal articleResearchpeer-review

  3. Hydroxylated Long-Chain Acylcarnitines are Biomarkers of Mitochondrial Myopathy

    Research output: Contribution to journalJournal articleResearchpeer-review

  4. Genotype and phenotype classification of 29 patients affected by Krabbe disease

    Research output: Contribution to journalJournal articleResearchpeer-review

  • Anna Pelet
  • Vaclava Skopova
  • Ulrike Steuerwald
  • Veronika Baresova
  • Mohammed Zarhrate
  • Jean-Marc Plaza
  • Ales Hnizda
  • Matyas Krijt
  • Olga Souckova
  • Flemming Wibrand
  • Guðrið Andorsdóttir
  • Fróði Joensen
  • David Sedlak
  • Anthony J Bleyer
  • Stanislav Kmoch
  • Stanislas Lyonnet
  • Marie Zikanova
View graph of relations

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.

Original languageEnglish
JournalHuman Molecular Genetics
Volume28
Issue number22
Pages (from-to)3805-3814
Number of pages10
ISSN0964-6906
DOIs
Publication statusPublished - 15 Nov 2019

ID: 58279778