Guanosine diphosphate-mannose:GlcNAc2-PP-dolichol mannosyltransferase deficiency (congenital disorders of glycosylation type Ik): five new patients and seven novel mutations
| Autor: | T, Dupré, S, Vuillaumier-Barrot, I, Chantret, H, Sadou Yayé, H S, Yayé, C, Le Bizec, A, Afenjar, C, Altuzarra, C, Barnérias, L, Burglen, P, de Lonlay, F, Feillet, S, Napuri, N, Seta, S E H, Moore |
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| Rok vydání: | 2010 |
| Předmět: |
Lipopolysaccharides
Male congenital hereditary and neonatal diseases and abnormalities medicine.medical_specialty Mannosyltransferase Glycosylation DNA Mutational Analysis Mannose Biology Mannosyltransferases medicine.disease_cause 03 medical and health sciences chemistry.chemical_compound Dolichol Congenital Disorders of Glycosylation Internal medicine Molecular genetics Genetics medicine Humans Genetics (clinical) Cells Cultured 030304 developmental biology 0303 health sciences Mutation Base Sequence 030305 genetics & heredity Infant Exons Fibroblasts Molecular biology 3. Good health Endocrinology chemistry Child Preschool Female Guanosine diphosphate mannose |
| Zdroj: | Journal of medical genetics. 47(11) |
| ISSN: | 1468-6244 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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