ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

González-Domínguez, Carlos; Fiesco-Roa, Moisés Ó; Gómez-Carmona, Samuel; Kleinert-Altamirano, Anke Paula Ingrid; He, Miao; Daniel, Earnest James Paul; Raymond, Kimiyo; Abreu-González, Melania; Manrique-Hernández, S.; González-Jaimes, Ana; Salinas-Marín, Roberta; Molina-Garay, Carolina; Carrillo‐Sánchez, Karol; Flores-Lagunes, Luis Leonardo; Jiménez-Olivares, M.; Muñoz-Rivas, Anallely; Cruz-Muñoz, Mario Ernesto; Ruiz–García, Matilde; Freeze, Hudson H.; Mora-Montes, Héctor M.; Aláez-Verson, Carmen; Martínez-Duncker, Iván

doi:10.3389/fgene.2021.744884

Cited by 3 publications

(1 citation statement)

References 32 publications

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“… 43 44 ALG1 encodes a transmembrane chitobiosyldiphosphodolichol β-mannosyltransferase, which mediates the biosynthesis of lipid-linked oligosaccharides. 45 46 ENTPD6 and ALG1 were both remarkably overexpressed in several human cancers, including HCC ( online supplemental figure 13A, B ). Patients with HCC with high ENTPD6 and ALG1 expression levels were likely to have poor overall survival outcomes ( online supplemental figure 13C ).…”

Section: Discussionmentioning

confidence: 99%

Dominant neoantigen verification in hepatocellular carcinoma by a single-plasmid system coexpressing patient HLA and antigen

Chen

et al. 2023

J Immunother Cancer

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BackgroundPrevious studies confirmed that most neoantigens predicted by algorithms do not work in clinical practice, and experimental validations remain indispensable for confirming immunogenic neoantigens. In this study, we identified the potential neoantigens with tetramer staining, and established the Co-HA system, a single-plasmid system coexpressing patient human leukocyte antigen (HLA) and antigen, to detect the immunogenicity of neoantigens and verify new dominant hepatocellular carcinoma (HCC) neoantigens.MethodsFirst, we enrolled 14 patients with HCC for next-generation sequencing for variation calling and predicting potential neoantigens. Then, the Co-HA system was established. To test the feasibility of the system, we constructed target cells coexpressing HLA-A*11:01 and the reportedKRASG12D neoantigen as well as specific T-cell receptor (TCR)-T cells. The specific cytotoxicity generated by this neoantigen was shown using the Co-HA system. Moreover, potential HCC-dominant neoantigens were screened out by tetramer staining and validated by the Co-HA system using methods including flow cytometry, enzyme-linked immunospot assay and ELISA. Finally, antitumor test in mouse mode and TCR sequencing were performed to further evaluate the dominant neoantigen.ResultsFirst, 2875 somatic mutations in 14 patients with HCC were identified. The main base substitutions were C>T/G>A transitions, and the main mutational signatures were 4, 1 and 16. The high-frequency mutated genes includedHMCN1,TTNandTP53. Then, 541 potential neoantigens were predicted. Importantly, 19 of the 23 potential neoantigens in tumor tissues also existed in portal vein tumor thrombi. Moreover, 37 predicted neoantigens restricted by HLA-A*11:01, HLA-A*24:02 or HLA-A*02:01 were performed by tetramer staining to screen out potential HCC-dominant neoantigens. HLA-A*24:02-restricted epitope 5'-FYAFSCYYDL-3' and HLA-A*02:01-restricted epitope 5'-WVWCMSPTI-3' demonstrated strong immunogenicity in HCC, as verified by the Co-HA system. Finally, the antitumor efficacy of 5'-FYAFSCYYDL-3'-specific T cells was verified in the B-NDG-B2mtm1Fcrntm1(mB2m)mouse and their specific TCRs were successfully identified.ConclusionWe found the dominant neoantigens with high immunogenicity in HCC, which were verified with the Co-HA system.

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Section: Discussionmentioning

confidence: 99%

Dominant neoantigen verification in hepatocellular carcinoma by a single-plasmid system coexpressing patient HLA and antigen

Chen

et al. 2023

J Immunother Cancer

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A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review

Xue,

Zhao,

et al. 2023

Molec Gen & Gen Med

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BackgroundThe congenital disorder of glycosylation associated with ALG1 (ALG1‐CDG) is a rare autosomal recessive disease. Due to the deficiency of β1,4 mannosyltransferase caused by pathogenic variants in ALG1 gene, the assembly and processing of glycans in the protein glycosylation pathway are impaired, resulting in a broad clinical spectrum with multi‐organ involvement. To raise awareness of clinicians for its manifestations and genotype, we here reported a new patient with a novel variant in ALG1 gene and reviewed the literature to study the genotype–phenotype correlation.MethodClinical characteristics were collected, and clinical exome sequencing was used to identify the causative variants. MutationTaster, PyMol, and FoldX were used to predict the pathogenicity, changes in 3D model molecular structure of protein, and changes of free energy caused by novel variants.ResultsThe proband was a 13‐month‐old Chinese Han male characterized by epileptic seizures, psychomotor development delay, muscular hypotonia, liver and cardiac involvement. Clinical exome sequencing revealed the biallelic compound heterozygosity variants, a previously reported variant c.434G>A (p.G145N, paternal) and a novel variant c.314T>A (p.V105N, maternal). The literature review found that in severe phenotypes, the incidences of clinical manifestations were significantly higher than that in mild phenotypes, including congenital nephrotic syndrome, agammaglobulinemia, and severe hydrops. Homozygous c.773C>T was a strongly pathogenic variant associated with a severe phenotype. When heterozygous for c.773C>T, patients with another variant leading to substitution in amino acids within the strongly conserved regions (c.866A>T, c.1025A>C, c.1182C>G) may cause a more severe phenotype than those within less‐conserved regions (c.434G>A, c.450C>G, c.765G>A, c.1287T>A). c.1129A>G, c.1076C>T, and c.1287T>A were more likely to be associated with a mild phenotype. The assessment of disease phenotypes requires a combination of genotype and clinical manifestations.ConclusionsThe case reported herein adds to the mutations identified in ALG1‐CDG and a review of this literature expands the study of the phenotypic and genotypic spectrum of this disorder.

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Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker

Martínez Duncker,

Mata-Salgado,

Shammas

et al. 2024

Front. Genet.

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This report outlines the case of a child affected by a type of congenital disorder of glycosylation (CDG) known as ALG2-CDG (OMIM 607906), presenting as a congenital myasthenic syndrome (CMS) caused by variants identified in ALG2, which encodes an α1,3-mannosyltransferase (EC 2.4.1.132) involved in the early steps of N-glycosylation. To date, fourteen cases of ALG2-CDG have been documented worldwide. From birth, the child experienced perinatal asphyxia, muscular weakness, feeding difficulties linked to an absence of the sucking reflex, congenital hip dislocation, and hypotonia. Over time, additional complications emerged, such as inspiratory stridor, gastroesophageal reflux, low intake, recurrent seizures, respiratory infections, an inability to maintain the head upright, and a global developmental delay. Whole genome sequencing (WGS) revealed the presence of two ALG2 variants in compound heterozygosity: a novel variant c.1055_1056delinsTGA p.(Ser352Leufs*3) and a variant of uncertain significance (VUS) c.964C>A p.(Pro322Thr). Additional studies, including determination of carbohydrate-deficient transferrin (CDT) revealed a mild type I CDG pattern and the presence of an abnormal transferrin glycoform containing a linear heptasaccharide consisting of one sialic acid, one galactose, one N-acetyl-glucosamine, two mannoses and two N-acetylglucosamines (NeuAc-Gal-GlcNAc-Man2-GlcNAc2), ALG2-CDG diagnostic biomarker, confirming the pathogenicity of these variants.

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ALG1-CDG Caused by Non-functional Alternative Splicing Involving a Novel Pathogenic Complex Allele

Cited by 3 publications

References 32 publications

Dominant neoantigen verification in hepatocellular carcinoma by a single-plasmid system coexpressing patient HLA and antigen

Dominant neoantigen verification in hepatocellular carcinoma by a single-plasmid system coexpressing patient HLA and antigen

A novel variant in ALG1 gene associated with congenital disorder of glycosylation: A case report and short literature review

Case report: Novel genotype of ALG2-CDG and confirmation of the heptasaccharide glycan (NeuAc-Gal-GlcNAc-Man2-GlcNAc2) as a specific diagnostic biomarker

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