Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing. Hum Mol Genet

Department of Neurology.
Human Molecular Genetics (Impact Factor: 6.39). 07/2012; 21(19):4151-61. DOI: 10.1093/hmg/dds123
Source: PubMed


Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N-glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families.

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    • "Deletion of DPAGT1 in mice leads to peri-implantation mortality (Marek et al. 1999), documenting its essential role at the earliest stages of mammalian development. In humans, mutations in DPAGT1 result in a significant reduction in GPT activity, giving rise to congenital disorders of glycosylation (CDG-Ij) and early mortality (Wu et al. 2003; Carrera et al. 2012; Timal et al. 2012). "
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    ABSTRACT: N-linked glycosylation (N-glycosylation) of proteins has long been associated with oncogenesis, but not until recently have the molecular mechanisms underlying this relationship begun to be unraveled. Here, we review studies describing how dysregulation of the N-glycosylation-regulating gene, DPAGT1, drives oral cancer. DPAGT1 encodes the first and rate-limiting enzyme in the assembly of the lipid-linked oligosaccharide precursor in the endoplasmic reticulum (ER) and thus mediates N-glycosylation of many cancer-related proteins. DPAGT1 controls N-glycosylation of E-cadherin, the major epithelial cell-cell adhesion receptor and a tumor suppressor, thereby affecting intercellular adhesion and cytoskeletal dynamics. DPAGT1 also regulates and is regulated by Wnt/β-catenin signaling, impacting the balance between proliferation and adhesion in homeostatic tissues. Thus, aberrant induction of DPAGT1 promotes a positive feedback network with Wnt/β-catenin that represses E-cadherin-based adhesion and drives tumorigenic phenotypes. Further, modification of receptor tyrosine kinases (RTKs) with N-glycans is known to control their surface presentation via the galectin lattice, and thus increased DPAGT1 expression likely contributes to abnormal activation of RTKs in oral cancer. Collectively, these studies suggest that dysregulation of the DPAGT1/Wnt/E-cadherin network underlies the etiology and pathogenesis of oral cancer.
    Glycobiology 04/2014; 24(7). DOI:10.1093/glycob/cwu031 · 3.15 Impact Factor
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    • "Intellectual disability was not noted, but the patient died at a very early age. The patient was also shown to have a severely reduced GlcNAc-transferase enzyme activity compared to control fibroblasts [Timal et al., 2012]. Congenital disorders of glycosylation type I (CDG-I) is a group of clinically and genetically highly heterogeneous neurometabolic diseases that is caused by deficiencies in the genes involved in N-linked glycosylation [Sparks and Krasnewich, 1993; updated August 09, 2012]. "
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    ABSTRACT: X-linked intellectual disability (XLID) is a heterogeneous condition associated with mutations in >100 genes, accounting for over 10% of all cases of intellectual impairment. The majority of XLID cases show nonsyndromic forms (NSXLID), in which intellectual disability is the sole clinically consistent manifestation. Here we performed X chromosome exome (X-exome) sequencing to identify the causative mutation in an NSXLID family with four affected male siblings and five unaffected female siblings. The X-exome sequencing at 88× coverage in one affected male sibling revealed a novel missense mutation (p.Tyr1074Cys) in the asparagine-linked glycosylation 13 homolog (ALG13) gene. Segregation analysis by Sanger sequencing showed that the all affected siblings were hemizygous and the mother was heterozygous for the mutation. Recently, a de novo missense mutation in ALG13 has been reported in a patient with X-linked congenital disorders of glycosylation type I. Our study reports the first case of NSXLID caused by a mutation in ALG13 involved in protein N-glycosylation. © 2013 Wiley Periodicals, Inc.
    American Journal of Medical Genetics Part A 02/2014; 164(1). DOI:10.1002/ajmg.a.36233 · 2.16 Impact Factor
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    • "As well as causing CMS, certain mutations in DPAGT1 have been reported to cause congenital disorder of glycosylation type 1J (CDG type 1J) [14–17]. This is one of a group of disorders caused by defects in the formation or processing of glycoproteins or glycolipids [18]. "
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    ABSTRACT: Mutations in DPAGT1 are a newly recognised cause of congenital myasthenic syndrome. DPAGT1 encodes an early component of the N-linked glycosylation pathway. Initially mutations in DPAGT1 have been associated with the onset of the severe multisystem disorder - congenital disorder of glycosylation type 1J. However, recently it was established that certain mutations in this gene can cause symptoms restricted to muscle weakness resulting from defective neuromuscular transmission. We report four cases from a large Iranian pedigree with prominent limb-girdle weakness and minimal craniobulbar symptoms who harbour a novel mutation in DPAGT1, c.652C>T, p.Arg218Trp. This myasthenic syndrome may mimic myopathic disorders and is likely under-diagnosed.
    Neuromuscular Disorders 04/2013; 23(6). DOI:10.1016/j.nmd.2013.03.003 · 2.64 Impact Factor
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