Pathogenic variants in uridine diphosphate nucleotidase ( CANT1 ) or glucuronyltransferase ( B3GAT3 ) causes a pseudodiastrophic dysplasia

Abstract

Calcium-activated uridine diphosphate nucleotidase 1 (CANT1) hydrolyzes UDP to uridine 5’-monophosphate (UMP) and an inorganic phosphate. Glucuronyltransferase-I (GlcAT-I) transfers a glucuronic acid (GlcA) from UDP-GlcA to galactose-galactose-xylose in core proteins of proteoglycans. Biallelic mutations in CANT1 or GlcAT-I cause Desbuquois dysplasia and multiple joint dislocations, respectively [1, 2]. Here, we identified the biallelic mutations of the CANT1 (Glu215Lys) or GlcAT-I (Arg169Trp/Arg225X) in the patients with pseudodiastrophic dysplasia [3], which is a severe skeletal dysplasia associated with prenatal manifestation and early lethality [4]. The GlcAT-I activities of recombinant Arg169Trp- and Arg225X-GlcAT-I proteins were significantly decreased compared to that of wild type-GlcAT-I [3]. Furthermore, cell lysates from the patient fibroblasts showed significantly reduced GlcAT-I activity compared with those from control fibroblasts. The amount of chondroitin sulfate and dermatan sulfate in the fibroblasts from a patient was markedly lower than that in control fibroblasts. Furthermore, the UDP-nucleotidase activity of recombinant Glu215Lys-CANT1was significantly reduced compared with that of wild type enzyme. These results suggest that the variants, Arg169Trp/Arg225X and Glu215Lys, in GlcAT-I and CANT1, respectively, are severe loss-of-function mutations, and cause the disturbance of biosynthesis of proteoglycans, which results in a pseudodiastrophic dysplasia with the significant phenotypic overlap of conditions within the biosynthetic pathway for proteoglycans. Refs. 1) Huber et al., Am J Hum Genet, 85, 706, 2009; 2) Baasanjav et al., Am J Hum Genet, 89, 15, 2011; 3) Byrne, Mizumoto et al., J Med Genet, 57, 454, 2020; 4) Yap et al., Am J Med Genet A, 170, 1363, 2016.