title: 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.
authors: Institute of Human Genetics, University of Cologne, Cologne, Germany, julia.schreml@uk-koeln.de.
authors: Julia
authors: J
authors: Schreml
authors: Burak
authors: B
authors: Durmaz
authors: Ozgur
authors: O
authors: Cogulu
authors: Katharina
authors: K
authors: Keupp
authors: Filippo
authors: F
authors: Beleggia
authors: Esther
authors: E
authors: Pohl
authors: Esther
authors: E
authors: Milz
authors: Mahmut
authors: M
authors: Coker
authors: Sema Kalkan
authors: SK
authors: Ucar
authors: Gudrun
authors: G
authors: Nürnberg
authors: Peter
authors: P
authors: Nürnberg
authors: Joachim
authors: J
authors: Kuhn
authors: Ferda
authors: F
authors: Ozkinay
mesh_terms: D003241:Consanguinity; D004392:Dwarfism / Q000235:genetics*; D059472:Exome; D005260:Female; D005808:Genes, Recessive; D008040:Genetic Linkage; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D010430:Pentosyltransferases / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype; D011509:Proteoglycans / Q000378:metabolism; D017422:Sequence Analysis, DNA; D013577:Syndrome; D014421:Turkey; D014965:X-Rays; D000097608:UDP Xylose-Protein Xylosyltransferase
chemical_list: D010430:Pentosyltransferases; D011509:Proteoglycans; D000097608:UDP Xylose-Protein Xylosyltransferase
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