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J. Biol. Chem., Vol. 283, Issue 12, 7354-7360, March 21, 2008

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Peters Plus Syndrome Is a New Congenital Disorder of Glycosylation and Involves Defective O-Glycosylation of Thrombospondin Type 1 Repeats^*

Daniel Hess, Jeremy J. Keusch, Saskia A. Lesnik Oberstein, Raoul C. M. Hennekam^¶||, and Jan Hofsteenge¹

From the Friedrich Miescher Institute for Biomedical Research, Basel CH-4058, Switzerland, the Center for Human and Clinical Genetics, Department of Clinical Genetics, K5-R, Leiden University Medical Center, 2300 RC Leiden, The Netherlands, the ^¶Clinical and Molecular Genetics Unit, Institute of Child Health, London WC1N 3JH, United Kingdom, and the ^||Department of Pediatrics, Academic Medical Center, 1105 AZ Amsterdam, The Netherlands

Peters Plus syndrome is an autosomal recessive disorder characterized by anterior eye chamber defects, disproportionate short stature, developmental delay, and cleft lip and/or palate. It is caused by splice site mutations in what was thought to be a β1,3-galactosyltransferase-like gene (B3GALTL). Recently, we and others found this gene to encode a β1,3-glucosyltransferase involved in the synthesis of the disaccharide Glc-β1,3-Fuc-O-that occurs on thrombospondin type 1 repeats of many biologically important proteins. No functional tests have been performed to date on the presumed glycosylation defect in Peters Plus syndrome. We have established a sensitive immunopurification-mass spectrometry method, using multiple reaction monitoring, to analyze O-fucosyl glycans. It was used to compare the reporter protein properdin from Peters Plus patients with that from control heterozygous relatives. In properdin from patients, we could not detect the Glc-β1,3-Fuc-O-disaccharide, and we only found Fuc-O-at all four O-fucosylation sites. In contrast, properdin from heterozygous relatives and a healthy volunteer carried the Glc-β1,3-Fuc-O-disaccharide. These data firmly establish Peters Plus syndrome as a new congenital disorder of glycosylation.

Received for publication, December 17, 2007 , and in revised form, January 16, 2008.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Tables S1–S4.

¹ To whom correspondence should be addressed: Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, Basel CH-4058, Switzerland. Tel.: 41-61-6974722; Fax: 41-61-6973976; E-mail: jan.hofsteenge{at}fmi.ch.

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