De novo synthesis of purines (DNPS) is a biochemical pathway that provides the purine bases for synthesis of essential biomolecules such as nucleic acids, energy transfer molecules, signaling molecules and various cofactors. Inborn errors of DNPS enzymes present with a wide spectrum of neurodevelopmental and neuromuscular abnormalities and accumulation of characteristic metabolic intermediates of the DNPS in body fluids and tissues. In this study, we present the second case of PAICS deficiency due to bi-allelic variants of PAICS gene encoding for a missense p.Ser179Pro and truncated p.Arg403Ter forms of the PAICS proteins. Two affected individuals were born at term after an uncomplicated pregnancy and delivery and presented later in life with progressive cerebral atrophy, epileptic encephalopathy, psychomotor retardation, and retinopathy. Plasma and urinary concentrations of dephosphorylated substrates of PAICS, AIr and CAIr were elevated, though they remained undetectable in skin fibroblasts. Both variants affect structural domains in SAICARs catalytic site and the oligomerization interface. In silico modeling predicted negative effects on PAICS oligomerization, enzyme stability and enzymatic activity. Consistent with these findings, affected skin fibroblasts were devoid of PAICS protein and enzyme activity. This was accompanied by alterations in contents of other DNPS proteins, which had co-localized in granular structures that are characteristic of purinosome formation. Our observation expands the clinical spectrum of PAICS deficiency from recurrent abortions and fatal neonatal form to later onset neurodevelopmental disorders. The rarity of this condition may be based on poor clinical recognition and limited access to specialized laboratory tests diagnostic for PAICS deficiency.

Department of Medical Genetics National Taiwan University Hospital Taipei Taiwan

Department of Neurology National Taiwan University Hospital Taipei Taiwan

Department of Ophthalmology College of Medicine National Taiwan University Hospital National Taiwan University Taipei Taiwan

Department of Paediatrics and Inherited Metabolic Disorders 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Department of Pediatrics National Taiwan University College of Medicine Taipei Taiwan

Department of Pediatrics National Taiwan University Hospital Taipei Taiwan

OMICS Mass Spectrometry Core Facility Biology Departments Faculty of Science Charles University BIOCEV Vestec Czech Republic

Zobrazit více v PubMed

An S, Kumar R, Sheets ED, Benkovic SJ. Reversible compartmentalization of de novo purine biosynthetic complexes in living cells. Science 2008;320:103–6. PubMed

Pedley AM, Boylan JP, Chan CY, Kennedy EL, Kyoung M, Benkovic SJ. Purine biosynthetic enzymes assemble into liquid-like condensates dependent on the activity of chaperone protein HSP90. J Biol Chem. 2022;298:101845. PubMed PMC

Jurecka A, Zikanova M, Kmoch S, Tylki-Szymanska A. Adenylosuccinate lyase deficiency. J Inherit Metab Dis. 2015;38:231–42. PubMed PMC

Marie S, Heron B, Bitoun P, Timmerman T, Van Den Berghe G, Vincent MF. AICA-ribosiduria: a novel, neurologically devastating inborn error of purine biosynthesis caused by mutation of ATIC. Am J Hum Genet. 2004;74:1276–81. PubMed PMC

Pelet A, Skopova V, Steuerwald U, Baresova V, Zarhrate M, Plaza JM, et al. PAICS deficiency, a new defect of de novo purine synthesis resulting in multiple congenital anomalies and fatal outcome. Hum Mol Genet. 2019;28:3805–14. PubMed

Ramond F, Rio M, Heron B, Imbard A, Marie S, Billiemaz K, et al. AICA-ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long-term update on the first case. J Inherit Metab Dis. 2020;43:1254–64. PubMed

Cremonesi A, Meili D, Rassi A, Poms M, Tavazzi B, Skopova V, et al. Improved diagnostics of purine and pyrimidine metabolism disorders using LC-MS/MS and its clinical application. Clin Chem Lab Med. 2023;61:1792–801. PubMed

Krijt M, Souckova O, Baresova V, Skopova V, Zikanova M. Metabolic tools for identification of new mutations of enzymes engaged in purine synthesis leading to neurological impairment. Folia Biol. 2019;65:152–7. PubMed

Galli J, Valente EM, Dewulf J, Franzoni A, Marie S, Plumari M, et al. Expanding the spectrum of clinical severity of AICA-ribosiduria: Report of two siblings with mild phenotype caused by a novel pathogenic variant in ATIC gene. Am J Med Genet A 2023;191:575–81. PubMed

Park JH, Och U, Braun T, Kriegel MF, Biskup S, Korall H, et al. Treatment of AICA ribosiduria by suppression of de novo purine synthesis. Mol Genet Metab. 2024;141:108124. PubMed

Baresova V, Krijt M, Skopova V, Souckova O, Kmoch S, Zikanova M. CRISPR-Cas9 induced mutations along de novo purine synthesis in HeLa cells result in accumulation of individual enzyme substrates and affect purinosome formation. Mol Genet Metab. 2016;119:270–7. PubMed

Souckova O, Skopova V, Baresova V, Sedlak D, Bleyer AJ, Kmoch S, et al. Metabolites of de novo purine synthesis: metabolic regulators and cytotoxic compounds. Metabolites 2022;12:1210. PubMed PMC

Wu ET, Hwu WL, Chien YH, Hsu C, Chen TF, Chen NQ, et al. Critical trio exome benefits in-time decision-making for pediatric patients with severe illnesses. Pediatr Crit Care Med. 2019;20:1021–6. PubMed

Chen PS, Lee NC, Sung CJ, Liu YW, Weng WC, Fan PC, et al. Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5. Mov Disord. 2023;38:2217–29. PubMed

Weissensteiner H, Forer L, Fuchsberger C, Schopf B, Kloss-Brandstatter A, Specht G, et al. mtDNA-Server: next-generation sequencing data analysis of human mitochondrial DNA in the cloud. Nucleic Acids Res. 2016;44:W64–9. PubMed PMC

Li SX, Tong YP, Xie XC, Wang QH, Zhou HN, Han Y, et al. Octameric structure of the human bifunctional enzyme PAICS in purine biosynthesis. J Mol Biol. 2007;366:1603–14. PubMed

Lyskov S, Chou FC, Conchuir SO, Der BS, Drew K, Kuroda D, et al. Serverification of molecular modeling applications: the Rosetta Online Server that Includes Everyone (ROSIE). PLoS ONE. 2013;8:e63906. PubMed PMC

Kmoch S, Hartmannova H, Stiburkova B, Krijt J, Zikanova M, Sebesta I. Human adenylosuccinate lyase (ADSL), cloning and characterization of full-length cDNA and its isoform, gene structure and molecular basis for ADSL deficiency in six patients. Hum Mol Genet. 2000;9:1501–13. PubMed

Zikanova M, Skopova V, Hnizda A, Krijt J, Kmoch S. Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency. Hum Mutat. 2010;31:445–55. PubMed

Landmann L. Deconvolution improves colocalization analysis of multiple fluorochromes in 3D confocal data sets more than filtering techniques. J Microsc. 2002;208:134–47. PubMed

Manders EMM, Verbeek FJ, Aten JA. Measurement of co-localization of objects in dual-colour confocal images. J Microsc. 1993;169:375–82. PubMed

Mouchegh K, Zikanova M, Hoffmann GF, Kretzschmar B, Kuhn T, Mildenberger E, et al. Lethal fetal and early neonatal presentation of adenylosuccinate lyase deficiency: observation of 6 patients in 4 families. J Pediatr. 2007;150:57–61.e2. PubMed

Baresova V, Skopova V, Sikora J, Patterson D, Sovova J, Zikanova M, et al. Mutations of ATIC and ADSL affect purinosome assembly in cultured skin fibroblasts from patients with AICA-ribosiduria and ADSL deficiency. Hum Mol Genet. 2012;21:1534–43. PubMed

Ng A, Uribe RA, Yieh L, Nuckels R, Gross JM. Zebrafish mutations in gart and paics identify crucial roles for de novo purine synthesis in vertebrate pigmentation and ocular development. Development 2009;136:2601–11. PubMed PMC

Phosphoribosylformylglycinamidine Synthase (PFAS) Deficiency: Clinical, Genetic and Metabolic Characterisation of a Novel Defect in Purine de Novo Synthesis