XYLT1 Mutations in Desbuquois Dysplasia Type 2

• Published in: American journal of human genetics Vol. 94; no. 3; pp. 405 - 414
• Main Authors: Bui, Catherine, Huber, Céline, Tuysuz, Beyhan, Alanay, Yasemin, Bole-Feysot, Christine, Leroy, Jules G., Mortier, Geert, Nitschke, Patrick, Munnich, Arnold, Cormier-Daire, Valérie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 06.03.2014; Cell Press; Elsevier (Cell Press); Elsevier
• Subjects: Adolescent; Adult; Biochemistry; Biochemistry, Molecular Biology; Biosynthesis; Bone and Bones - metabolism; Cell culture; Child; Consanguinity; Craniofacial Abnormalities - genetics; DNA, Complementary - metabolism; Dwarfism - genetics; Exome; Female; Fibroblasts - metabolism; Genes; Genetic disorders; Genetic Predisposition to Disease; Genetics; Homozygote; Human genetics; Humans; Joint Instability - genetics; Life Sciences; Male; Microsatellite Repeats - genetics; Mutation; Ossification, Heterotopic - genetics; Pentosyltransferases - genetics; Pentosyltransferases - metabolism; Polydactyly - genetics; Proteoglycans - metabolism; Sequence Analysis, DNA; UDP Xylose-Protein Xylosyltransferase
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2014.01.020

Desbuquois dysplasia (DBQD) is a severe condition characterized by short stature, joint laxity, and advanced carpal ossification. Based on the presence of additional hand anomalies, we have previously distinguished DBQD type 1 and identified CANT1 (calcium activated nucleotidase 1) mutations as responsible for DBQD type 1. We report here the identification of five distinct homozygous xylosyltransferase 1 (XYLT1) mutations in seven DBQD type 2 subjects from six consanguineous families. Among the five mutations, four were expected to result in loss of function and a drastic reduction of XYLT1 cDNA level was demonstrated in two cultured individual fibroblasts. Because xylosyltransferase 1 (XT-I) catalyzes the very first step in proteoglycan (PG) biosynthesis, we further demonstrated in the two individual fibroblasts a significant reduction of cellular PG content. Our findings of XYLT1 mutations in DBQD type 2 further support a common physiological basis involving PG synthesis in the multiple dislocation group of disorders. This observation sheds light on the key role of the XT-I during the ossification process.