Universität zu Köln

Schreml, Julia, Durmaz, Burak, Cogulu, Ozgur, Keupp, Katharina, Beleggia, Filippo ORCID: 0000-0003-0234-7094, Pohl, Esther, Milz, Esther, Coker, Mahmut, Ucar, Sema Kalkan ORCID: 0000-0001-9574-7841, Nuernberg, Gudrun, Nuernberg, Peter, Kuhn, Joachim and Ozkinay, Ferda (2014). The missing link: an autosomal recessive short stature syndrome caused by a hypofunctional XYLT1 mutation. Hum. Genet., 133 (1). S. 29 - 40. NEW YORK: SPRINGER. ISSN 1432-1203

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Schreml, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Durmaz, Burak UNSPECIFIED UNSPECIFIED UNSPECIFIED Cogulu, Ozgur UNSPECIFIED UNSPECIFIED UNSPECIFIED Keupp, Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Beleggia, Filippo UNSPECIFIED orcid.org/0000-0003-0234-7094 UNSPECIFIED Pohl, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Milz, Esther UNSPECIFIED UNSPECIFIED UNSPECIFIED Coker, Mahmut UNSPECIFIED UNSPECIFIED UNSPECIFIED Ucar, Sema Kalkan UNSPECIFIED orcid.org/0000-0001-9574-7841 UNSPECIFIED Nuernberg, Gudrun UNSPECIFIED UNSPECIFIED UNSPECIFIED Nuernberg, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Kuhn, Joachim UNSPECIFIED UNSPECIFIED UNSPECIFIED Ozkinay, Ferda UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-452244
DOI:	10.1007/s00439-013-1351-y
Journal or Publication Title:	Hum. Genet.
Volume:	133
Number:	1
Page Range:	S. 29 - 40
Date:	2014
Publisher:	SPRINGER
Place of Publication:	NEW YORK
ISSN:	1432-1203
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EHLERS-DANLOS-SYNDROME; AGE-RELATED-CHANGES; GALACTOSYLTRANSFERASE-I; XYLOSYLTRANSFERASE ACTIVITY; SULFATE PROTEOGLYCAN; EXTRACELLULAR-MATRIX; MOLECULAR DIVERSITY; PROGEROID VARIANT; IDENTIFICATION; BIOSYNTHESIS Multiple languages Genetics & Heredity Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/45224