Dataset Information

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

ABSTRACT: Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a ?1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been described with varying degrees of clinical severity. We identified and characterized 39 previously unreported cases of ALG1-CDG from 32 families and add 26 new mutations. Pathogenicity of each mutation was confirmed based on its inability to rescue impaired growth or hypoglycosylation of a standard biomarker in an alg1-deficient yeast strain. Using this approach we could not establish a rank order comparison of biomarker glycosylation and patient phenotype, but we identified mutations with a lethal outcome in the first two years of life. The recently identified protein-linked xeno-tetrasaccharide biomarker, NeuAc-Gal-GlcNAc2 , was seen in all 27 patients tested. Our study triples the number of known patients and expands the molecular and clinical correlates of this disorder.

SUBMITTER: Ng BG

PROVIDER: S-EPMC4907823 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

Ng Bobby G BG Shiryaev Sergey A SA Rymen Daisy D Eklund Erik A EA Raymond Kimiyo K Kircher Martin M Abdenur Jose E JE Alehan Fusun F Midro Alina T AT Bamshad Michael J MJ Barone Rita R Berry Gerard T GT Brumbaugh Jane E JE Buckingham Kati J KJ Clarkson Katie K Cole F Sessions FS O'Connor Shawn S Cooper Gregory M GM Van Coster Rudy R Demmer Laurie A LA Diogo Luisa L Fay Alexander J AJ Ficicioglu Can C Fiumara Agata A Gahl William A WA Ganetzky Rebecca R Goel Himanshu H Harshman Lyndsay A LA He Miao M Jaeken Jaak J James Philip M PM Katz Daniel D Keldermans Liesbeth L Kibaek Maria M Kornberg Andrew J AJ Lachlan Katherine K Lam Christina C Yaplito-Lee Joy J Nickerson Deborah A DA Peters Heidi L HL Race Valerie V Régal Luc L Rush Jeffrey S JS Rutledge S Lane SL Shendure Jay J Souche Erika E Sparks Susan E SE Trapane Pamela P Sanchez-Valle Amarilis A Vilain Eric E Vøllo Arve A Waechter Charles J CJ Wang Raymond Y RY Wolfe Lynne A LA Wong Derek A DA Wood Tim T Yang Amy C AC Matthijs Gert G Freeze Hudson H HH

Human mutation 20160321 7

Congenital disorders of glycosylation (CDG) arise from pathogenic mutations in over 100 genes leading to impaired protein or lipid glycosylation. ALG1 encodes a β1,4 mannosyltransferase that catalyzes the addition of the first of nine mannose moieties to form a dolichol-lipid linked oligosaccharide intermediate required for proper N-linked glycosylation. ALG1 mutations cause a rare autosomal recessive disorder termed ALG1-CDG. To date 13 mutations in 18 patients from 14 families have been descri ...[more]

PMID: 26931382

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Project description:BackgroundSLC39A8, a gene located on chromosome 4q24, encodes for the manganese (Mn) transporter ZIP8 and its detrimental variants cause a type 2 congenital disorder of glycosylation (CDG). The common SLC39A8 missense variant A391T is associated with increased risk for multiple neurological and systemic disorders and with decreased serum Mn. Patients with SLC39A8-CDG present with different clinical and neuroradiological features linked to variable transferrin glycosylation profile. Galactose and Mn supplementation therapy results in the biochemical and clinical amelioration of treated patients.ResultsHere, we report clinical manifestations, neuroradiological features and glycophenotypes associated with novel SLC39A8 variants (c.1048G > A; p.Gly350Arg and c.131C > G; p.Ser44Trp) in two siblings of the same Italian family. Furthermore, we describe a third patient with overlapping clinical features harbouring the homozygous missense variant A391T. The clinical phenotype of the three patients was characterized by severe developmental disability, dystonic postural pattern and dyskinesia with a more severe progression of the disease in the two affected siblings. Neuroimaging showed a Leigh syndrome-like pattern involving the basal ganglia, thalami and white matter. In the two siblings, atrophic cerebral and cerebellum changes consistent with SLC39A8-CDG were detected as well. Serum transferrin isoelectric focusing (IEF) yielded variable results with slight increase of trisialotransferrin isoforms or even normal pattern. MALDI-MS showed the presence of hypogalactosylated transferrin N-glycans, spontaneously decreasing during the disease course, only in one affected sibling. Total serum N-glycome depicted a distinct pattern for the three patients, with increased levels of undergalactosylated and undersialylated precursors of fully sialylated biantennary glycans, including the monosialo-monogalacto-biantennary species A2G1S1.ConclusionsClinical, MRI and glycosylation features of patients are consistent with SLC39A8-CDG. We document two novel variants associated with Leigh syndrome-like disease presentation of SLC39A8-CDG. We show, for the first time, a severe neurological phenotype overlapping with that described for SLC39A8-CDG in association with the homozygous A391T missense variant. We observed a spontaneous amelioration of transferrin N-glycome, highlighting the efficacy of MS-based serum glycomics as auxiliary tool for the diagnosis and clinical management of therapy response in patients with SLC39A8-CDG. Further studies are needed to analyse more in depth the influence of SLC39A8 variants, including the common missense variant, on the expression and function of ZIP8 protein, and their impact on clinical, biochemical and neuroradiological features.

Dataset Information

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

Publications

ALG1-CDG: Clinical and Molecular Characterization of 39 Unreported Patients.

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