The missing “link”: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation

Abstract

Proteoglycan (PG) synthesis begins with the sequential addition of a "linker chain", made up of four sugar residues, to a specific region of a core protein. Defects in the enzymes catalyzing steps two to four of the linker chain synthesis have been shown to cause autosomal recessive human phenotypes while no mutation has yet been reported in humans for the xylosyltransferases 1 and 2 (XT1 and XT2), the initiating enzymes in the linker chain formation. Here, we present a consanguineous Turkish family with two affected individuals presenting with short stature, distinct facial features, alterations of fat distribution, and moderate intellectual disability. X-rays showed only mild skeletal changes in the form of a short femoral neck, stocky and plump long bones and thickened ribs. Using a combination of whole-exome sequencing (WES), determination of homozygous stretches by WES variants, and classical linkage analysis, we identified the homozygous missense mutation c.C1441T in XYLT1, encoding XT1, within a large homozygous stretch on chromosome 16p13.12-p12.1. The mutation co-segregated with the phenotype in the family, is not found in over 13,000 alleles in the exome variant server and is predicted to change a highly conserved arginine at position 481 (p.R481W) located in the putative catalytical domain. Immunostaining of primary patient fibroblasts showed a loss of predominance of Golgi localization in mutant cells. Moreover, western blot analysis of decorin in cell culture supernatant demonstrated glycosylation differences between patient and control cells. Our data provide evidence that functional alterations of XT1 cause an autosomal recessive short stature syndrome associated with intellectual disability.

Human Genetic Disorders and Knockout Mice Deficient in Glycosaminoglycan

“…Mutation in XYLT1 causes an autosomal recessive short stature syndrome characterized by alterations in the distribution of fat, intellectual disabilities, and skeletal abnormalities including a short stature and femoral neck, thickened ribs, plump long bones, and distinct facial features [56]. The homozygous mutation in XYLT1 gives rise to the substitution of the amino acid, p.Arg481Trp in the deduced catalytic domain, which results in decorin without a DS side chain in addition to mature decorin-PG with a DS chain from the fibroblasts of the patient [56].…”

“…The homozygous mutation in XYLT1 gives rise to the substitution of the amino acid, p.Arg481Trp in the deduced catalytic domain, which results in decorin without a DS side chain in addition to mature decorin-PG with a DS chain from the fibroblasts of the patient [56]. In addition, the mutant XYLT1 is diffusely localized in the cytoplasm and partially in the Golgi in the fibroblasts of the patient.…”

Homozygosity for Frameshift Mutations in XYLT2 Result in a Spondylo-Ocular Syndrome with Bone Fragility, Cataracts, and Hearing Defects

“…For example, in animal models and humans, impaired XYLT1 function is associated with cartilage abnormalities due to defects in endochondral ossification and growth. 7,8,11 These observations suggest that XYLT1 is critically important for growth cartilage and that its deficiency is not compensated for by XYLT2 in this tissue. The genetic syndromes characterized by osteoporosis, eye involvement with or without hearing impairment, and intellectual disability include osteoporosis pseudoglioma (OPPG [MIM: 259770]) syndrome and spondylo-ocular syndrome (SOS [MIM: 605822]).…”

“…5 Three additional sugar residues of the linker region are then added as galactose-galactoseglucuronic acid. Defects at each step of these sugar additions causes various autosomal-recessive disorders (MIM: 604327, 606374), 6,7 illustrating the importance of PG in tissue homeostasis. XYLT1 and XYLT2 are very similar in function and are co-expressed in many tissues, but some temporal, spatial, and tissue-specific differences in expression exist 5,8 and at the cellular level one or the other can be exclusively expressed.…”

News on Clinical Details and Treatment in PGM1-CDG

“…In addition, mutations in XYLT1 have been shown to cause short stature (Schreml et al 2014). The encoded protein xylosyltransferase (XT1) is necessary to start proteoglycan production with the common linker: protein-Ser-O-Xyl-Gal-Gal-GlcA, i.e., requiring two galactose molecules.…”