Am J Med Genet A 2017 Jul 30;173(7):1773-1781. Epub 2017 Apr 30.
Department of Paediatrics, College of Medicine and Health Sciences, Al-Ain, United Arab Emirates.
Desbuquois syndrome is a heterogeneous rare type of skeletal dysplasia with a prevalence of less than 1 in 1,000,000 individuals. It is characterized by short-limbed dwarfism, dysmorphic facial features, and severe joint laxity. Two types have been recognized depending on the presence of distinctive carpal and phalangeal features. Mutations in the calcium activated nucleotidase 1 (CANT1) have been found to be responsible for type I and lately, for the Kim type of Desbuquois dysplasia. In addition, a number of Desbuquois dysplasia type II patients have been attributed to mutations in xylosyltransferase 1, encoded by the XYLT1 gene, an enzyme that catalyzes the transfer of UDP-xylose (a marker of cartilage destruction) to serine residues of an acceptor protein, essential for the biosynthesis of proteoglycans. We report here a patient with features consistent with Desbuquois dysplasia II including short long bones, flat face, mild monkey wrench appearance of the femoral heads. Whole exome sequencing revealed a novel homozygous duplication of a single nucleotide in XYLT1 gene (c.2169dupA). This variant is predicted to result in a frame-shift and stop codon p.(Val724Serfs*10) within the xylosyltransferase catalytic domain. Immunoflourescence staining of HeLa cells transfected with mutated XYLT1 plasmids constructs of the current as well as the previously reported missense mutations (c.1441C>T, p.(Arg481Trp) and c.1792C>T, p.(Arg598Cys)), revealed aberrant subcellular localization of the enzyme compared to wild-type, suggesting endoplasmic reticulum retention of these mutants as the likely mechanism of disease.