Deficiency of dolichol-phosphate-mannose synthase-1 causes congenital disorder of glycosylation type Ie

Imbach, Timo
Schenk, Barbara
Schollen, Els
Burda, Patricie
Stutz, Andreas
Grünewald, Stephanie
Bailie, Nicola M.
King, Mary D.
Jaeken, Jaak
Matthijs, Gert
Berger, Eric G.
Aebi, Markus
Hennet, Thierry

¹Institute of Physiology, University of Zürich, 8057 Zürich, Switzerland
²Institute of Microbiology, Swiss Federal Institute of Technology, 8092 Zürich, Switzerland
³Center for Human Genetics, Catholic University Leuven, 3000 Leuven, Belgium
⁴Neurology Department, The Children's Hospital, Dublin 1, Ireland
⁵Department of Pediatrics, University Hospital Leuven, 3000 Leuven, Belgium

Address correspondence to: Thierry Hennet, Institute of Physiology, Winterthurerstrasse 190, CH-8057 Zürich, Switzerland. Phone: 41-1-635-5080; Fax: 41-1-635-6814; E-mail: [email protected].

Patricie Burda's present address is: Howard Hughes Medical Institute, Division of Cellular and Molecular Medicine, University of California-San Diego, 9500 Gilman Drive, La Jolla, California 92093, USA.

Timo Imbach and Barbara Schenk contributed equally to this work.

Received for publication October 15, 1999, and accepted in revised form December 7, 1999.

Journal of Clinical Investigation 105(2):p 233-239, January 2000.

Congenital disorders of glycosylation (CDG), formerly known as carbohydrate-deficient glycoprotein syndromes, lead to diseases with variable clinical pictures. We report the delineation of a novel type of CDG identified in 2 children presenting with severe developmental delay, seizures, and dysmorphic features. We detected hypoglycosylation on serum transferrin and cerebrospinal fluid β-trace protein. Lipid-linked oligosaccharides in the endoplasmic reticulum of patient fibroblasts showed an accumulation of the dolichyl pyrophosphate Man₅GlcNAc₂ structure, compatible with the reduced dolichol-phosphate-mannose synthase (DolP-Man synthase) activity detected in these patients. Accordingly, 2 mutant alleles of the DolP-Man synthase DPM1 gene, 1 with a 274C>G transversion, the other with a 628delC deletion, were detected in both siblings. Complementation analysis using DPM1-null murine Thy1-deficient cells confirmed the detrimental effect of both mutations on the enzymatic activity. Furthermore, mannose supplementation failed to improve the glycosylation status of DPM1-deficient fibroblast cells, thus precluding a possible therapeutic application of mannose in the patients. Because DPM1 deficiency, like other subtypes of CDG-I, impairs the assembly of N-glycans, this novel glycosylation defect was named CDG-Ie.