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.

AICA‐ribosiduria due to ATIC deficiency: Delineation of the phenotype with three novel cases, and long‐term update on the first case

“…5 Moreover, PAICS deficiency has been recently reported for the first time in human, in two siblings affected by multiple congenital malformations with fatal neonatal outcome. 6 Finally, bifunctional purine biosynthesis protein PURH (ATIC) is a homodimer which catalyzes the penultimate and final steps of DNPS through its phosphoribosylaminoimidazolecarboxamide formyltransferase F I G U R E 1 De novo purine biosynthesis pathway. The six enzymes composing the purinosome are represented schematically (and not representatively of the actual tridimensional structure) in gray shapes, with their corresponding names in white characters.…”

Transcriptome and metabolome analysis of crGART, a novel cell model of de novo purine synthesis deficiency: Alterations in CD36 expression and activity

“…Until quite recently, only one patient had been identified with AICA-ribosiduria (ATIC deficiency), but now, three more individuals (two are siblings) have been identified [10]. Finally, two individuals (siblings) have been identified with PAICS deficiency [11]. ADSL deficiency is a spectrum disorder with three generalized classes: neonatal fatal, severe, or mild to moderate.…”

Nwd1 regulates neuronal differentiation and migration through purinosome formation in the developing cerebral cortex

“…Recently, PAICS deficiency was reported in humans. Patients carrying a homozygous missense mutation in the PAICS gene exhibit multiple severe malformations, including a small body and craniofacial dysmorphism, resulting in early neonatal death (Pelet et al, 2019). Although inactivating mutations in the human NWD1…”

“…PAICS deficiency in humans was recently reported. A missense mutation in Paics causes the severe phenotype with multiple malformations, including a small body, short neck, and craniofacial dysmorphism, resulting in early neonatal death (Pelet et al, 2019). To date, however, there is no direct evidence of the localization or physiological function of purinosomes during brain development.…”