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Pathogenic variants in uridine diphosphate nucleotidase ( CANT1 ) or glucuronyltransferase ( B3GAT3 ) causes a pseudodiastrophic dysplasia
Author(s) -
Mizumoto Shuji,
Byrne Alicia,
Sugahara Kazuyuki,
Yamada Shuhei,
Scott Hamish
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.00175
Subject(s) - chemistry , biochemistry , enzyme , hypophosphatasia , uridine diphosphate , alkaline phosphatase
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.