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Identification of the molecular origins of disease in a cohort of patients with suspected congenital disorders of glycosylation (CDG)

Abstract : Background: Congenital disorders of glycosylation (CDGs) are rare inherited diseases caused by mutations in genes required for glycoconjugate biosynthesis. CDG clinical presentations range from monosystemic to multiorgan failure. Often these diseases are diagnosed biochemically by the presence of hypoglycosylated serum proteins. Molecular diagnosis of CDG is crucial for both antenatal diagnostics and development of treatment strategies. Aims: To determine the molecular origins of disease in suspected CDG patients. Two cases were chosen for more extended biochemical explorations in order to investigate the consequences of the mutations and possible treatment strategies. Subjects/Methods: Biochemical explorations of skin biopsy fibroblasts from a cohort of patients presenting with signs suggestive of CDG, and serum protein hypoglycosylation. Results and conclusions: In the first study, a patient presented with multisystemic disease suggesting CDG. Fibroblasts revealed both truncated dolichol-linked oligosaccharides and polymannose-type N-glycans. Mutations in the dehydrodolichol diphosphate synthase (DHDDS) gene were found as well as low DHDDS activity and dolichol phosphate levels. As previous cases of DHDDS-CDG present with retinitis pigmentosa only, we describe the first case of a CDG syndrome associated with mutations in DHDDS. In the second study, two siblings presented with thrombocytopenia and CNS signs. A biallelic mutation in the CMP-sialic acid transporter gene (SLC35A1) was associated with hyposialylated serum glycoproteins. Altered glycosphingolipid profiles were seen and sialic acid supplementation of patient cells increased the appearance of gangliosides
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Submitted on : Friday, December 1, 2017 - 8:56:49 AM
Last modification on : Sunday, October 25, 2020 - 7:34:57 PM

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  • HAL Id : tel-01653081, version 1

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Sahar Sabry Zaki Tlep. Identification of the molecular origins of disease in a cohort of patients with suspected congenital disorders of glycosylation (CDG). Tissues and Organs [q-bio.TO]. Université Pierre et Marie Curie - Paris VI, 2016. English. ⟨NNT : 2016PA066715⟩. ⟨tel-01653081⟩

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