† These authors contributed equally. Received: August 2, 2019. Revised: September 10, 2019. Accepted: September 12, 2019 © The Author(s) 2019. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com 3805 Human Molecular Genetics, 2019, Vol. 28, No. 22 3805–3814 doi: 10.1093/hmg/ddz237 Advance Access Publication Date: 10 October 2019 General Article GENERAL ARTICLE PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome Anna Pelet 1,† , Vaclava Skopova 2,† , Ulrike Steuerwald 3 , Veronika Baresova 2 , Mohammed Zarhrate 1 , Jean-Marc Plaza 1 , Ales Hnizda 4 , Matyas Krijt 2 , Olga Souckova 2 , Flemming Wibrand 5 , Guðrið Andorsdóttir 6 , Fróði Joensen 3 , David Sedlak 7 , Anthony J Bleyer 2,8 , Stanislav Kmoch 2 , Stanislas Lyonnet 1 and Marie Zikanova 2, * 1 Laboratory Embryology and Genetics of Congenital Malformation, INSERM UMR1163, Imagine Institute, Université de Paris, F-75015 Paris, France, 2 Research Unit for Rare Diseases, Department of Paediatrics and Adolescent Medicine, First Faculty of Medicine, Charles University and General University Hospital, 12808 Prague, Czech Republic, 3 Pediatric Unit, Medical Department, The Faroese Hospital System, FO 100 Tórshavn, Faroe Islands, 4 Department of Biochemistry, University of Cambridge, CB2 1TN Cambridge, UK, 5 Department of Clinical Genetics, Rigshospitalet, 2100 Copenhagen, Denmark, 6 FarGen, The Genetic Biobank of the Faroe Islands, FO 100 Tórshavn, Faroe Islands, 7 CZ-OPENSCREEN, Institute of Molecular Genetics, Czech Academy of Sciences, 140 00 Prague, Czech Republic. 8 Section on Nephrology, Wake Forest School of Medicine, 271 03 Winston-Salem, NC, USA *To whom correspondence should be addressed at: Department of Pediatrics and Adolescent Medicine, Ke Karlovu 2, 12808 Prague 2, Czech Republic. Tel: +420224967208; Email: marie.zikanova@lf1.cuni.cz 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 Downloaded from https://academic.oup.com/hmg/article/28/22/3805/5584440 by Siena College user on 26 February 2023