Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations (original) (raw)

Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations

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  1. T Dupré1,2,3,
  2. S Vuillaumier-Barrot1,2,3,
  3. I Chantret2,3,
  4. H S Yayé1,
  5. C Le Bizec1,
  6. A Afenjar4,
  7. C Altuzarra5,
  8. C Barnérias6,
  9. L Burglen7,
  10. P de Lonlay8,9,
  11. F Feillet10,
  12. S Napuri11,
  13. N Seta1,8,
  14. S E H Moore2,3
  15. 1Biochimie Métabolique et Cellulaire, Hôpital Bichat-Claude Bernard, AP-HP, Paris, France
  16. 2INSERM U773 CRB3, Paris, France
  17. 3Université Denis Diderot Paris 7, Paris, France
  18. 4Service de Neuropédiatrie et Pathologie du Développement, Hôpital Armand Trousseau, AP-HP, Paris, France
  19. 5Service de Pédiatrie, Hôpital Saint Jacques, Besançon, France
  20. 6Service de Neuropédiatrie and Centre de Référence des Maladies Neuromusculaires, Hôpital Necker—Enfants Malades, AP-HP, Paris, France
  21. 7Service de Génétique, Génétique Clinique-Neurogénétique, Hôpital Armand Trousseau, AP-HP, Paris, France
  22. 8Université Paris Descartes, Paris, France
  23. 9Département de Pédiatrie, Hôpital Necker—Enfants Malades, AP-HP, Paris, France
  24. 10Centre de Référence des Maladies Héréditaires du Métabolisme CHU Brabois Enfant, Vandoeuvre les Nancy, France
  25. 11Service: Explorations Fonctionnelles Neurologiques Hôpital Sud-Rennes, RENNES, France
  26. Correspondence to Dr Thierry Dupré, Laboratoire Biochimie A, INSERM, 3ème étage de la tour, 46 rue Henri Huchard, 75018 Paris, France; thierry.dupre{at}bch.aphp.fr

Abstract

Background In type I congenital disorders of glycosylation (CDG I), proteins necessary for the biosynthesis of the lipid-linked oligosaccharide (LLO) required for protein N-glycosylation are defective. A deficiency in guanosine diphosphate-mannose: GlcNAc2-PP-dolichol mannosyltransferase-1 (MT-1) causes CDG Ik (OMIM 608540), and only five patients, with severe multisystemic clinical presentations, have been described with this disease.

Objective To characterise genetic, biochemical and clinical data in five new CDG Ik cases and compare these findings with those of the five previously described patients.

Methods LLO biosynthesis was examined in skin biopsy fibroblasts, mannosyltransferases were assayed in microsomes prepared from these cells, and _ALG1_-encoding MT-1 was sequenced at the DNA and complementary DNA levels. Clinical data for the five new patients were collated.

Results Cells from five patients with non-typed CDG I revealed accumulations of GlcNAc2-PP-dolichol, the second intermediate in the biosynthesis of LLO. Assay of MT-1, -2 and -3, the first three mannosyltransferases required for extension of this intermediate, demonstrated only MT-1 to be deficient. DNA sequencing of ALG1 revealed nine different mutations, seven of which have not been previously reported. Clinical presentations are severe, with dysmorphias, CNS involvement and ocular disturbances being prevalent.

Conclusions 5 patients with CDG Ik are described, and their identification reveals that in France, this disease and CDG Ib (mannose phosphate isomerase deficiency: OMIM 602579) are the most frequently diagnosed CDG I after CDG Ia (phosphomannomutase 2 deficiency: OMIM 601785) and substantiate previous observations indicating that this disease presents at the severe end of the CDG I clinical spectrum.

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