B4GALT1‐congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature

Staretz‐Chacham, Orna; Noyman, Iris; Wormser, Ohad; Quider, Abed Abu; Hazan, Guy; Morag, Iris; Hadar, Noam; Raymond, Kimiyo; Birk, Ohad S.; Ferreira, Carlos R.; Koifman, Arie

doi:10.1111/cge.13735

Cited by 9 publications

(6 citation statements)

References 20 publications

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“…A rare homozygous frame shift insertion in B4GALT1 that predicts a nonfunctional truncated protein was reported to cause congenital disorder of glycosylation type 2 (CDGII) (28)(29)(30)(31). Three of the six reported CDGII patients exhibited, among other traits, abnormal coagulation and very high levels of aspartate transaminase (AST).…”

Section: Association Analyses Identify B4galt1 Pasn352ser As a New Ld...mentioning

confidence: 99%

Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen

Montasser

Hout

Miloscio

et al. 2021

Science

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Rare variants and blood LDL cholesterol A current goal in genomics is to identify genetic variation associated with actionable traits of clinical concern. Through exome sequencing of an Old Order Amish population, Montasser et al . identified a genetic variant that results in an amino acid change in the beta-1,4-galactosyltransferase 1 protein and is correlated with lower levels of cardiovascular disease. Investigation of the mutant protein showed that it affects genes associated with low-density lipoprotein cholesterol (LDL-C), and mice engineered to express the mutant protein exhibited a 38% decrease in blood LDL-C levels. This study suggests that such genomic sequencing and analysis can link genotype to phenotype and identify potentially clinically actionable pathways to treat disease. —LMZ

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Section: Association Analyses Identify B4galt1 Pasn352ser As a New Ld...mentioning

confidence: 99%

Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen

Montasser

Hout

Miloscio

et al. 2021

Science

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“…A similar N-glycoprofile was detected in B4GALT1-CDG with the presence of increased levels of truncated glycans with terminal N-acetylhexosamines (Hex3HexNAc4, Hex3HexNAc5, Hex3HexNAc5Fuc1) and bi-antennary glycans missing both galactose and sialic acid moieties (Hex4HexNAc4NeuAc1). The difference between B4GALT1-CDG and SLC35A2-CDG lies mainly in the elevated level of Hex3HexNAc4Fuc1 glycan in B4GALT1-CDG [33,34], which was not observed in increased relative intensity in either presented or previously identified SLC35A2-CDG patients. An increase in several complex truncated glycans lacking galactose and sialic acid was reported in TMEM165-CDG [35][36][37]; however, neither the serum nor Tf N-glycoprofile of SLC35A2-CDG patients reveals increased levels of monosialylated biantennary glycans with two galactoses (Hex5HexNAc4NeuAc1 ± Fuc1) which were identified in TMEM165-CDG.…”

Section: Discussionmentioning

confidence: 65%

N-Glycoprofiling of SLC35A2-CDG: Patient with a Novel Hemizygous Variant

et al. 2023

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Congenital disorders of glycosylation (CDG) are a group of rare inherited metabolic disorders caused by a defect in the process of protein glycosylation. In this work, we present a comprehensive glycoprofile analysis of a male patient with a novel missense variant in the SLC35A2 gene, coding a galactose transporter that translocates UDP-galactose from the cytosol to the lumen of the endoplasmic reticulum and Golgi apparatus. Isoelectric focusing of serum transferrin, which resulted in a CDG type II pattern, was followed by structural analysis of transferrin and serum N-glycans, as well as the analysis of apolipoprotein CIII O-glycans by mass spectrometry. An abnormal serum N-glycoprofile with significantly increased levels of agalactosylated (Hex3HexNAc4-5 and Hex3HexNAc5Fuc1) and monogalactosylated (Hex4HexNAc4 ± NeuAc1) N-glycans was observed. Additionally, whole exome sequencing and Sanger sequencing revealed de novo hemizygous c.461T > C (p.Leu154Pro) mutation in the SLC35A2 gene. Based on the combination of biochemical, analytical, and genomic approaches, the set of distinctive N-glycan biomarkers was characterized. Potentially, the set of identified aberrant N-glycans can be specific for other variants causing SLC35A2-CDG and can distinguish this disorder from the other CDGs or other defects in the galactose metabolism.

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“…Staretz-Chacham et al described three additional patients homozygous for a novel mutation in β4GALT1 (p.Arg21Trp), located within its transmembrane domain. These patients showed a uniform clinical presentation with intellectual disability, profound pancytopenia requiring chronic treatment, and novel features including pulmonary hypertension and nephrotic syndrome [ 60 ]. In addition, Giannini et al generated a B4galt1 -/- mouse and observed that β4GALT1 deficiency increases the number of differentiated MKs.…”

Section: Disorders Of Glycosylation Associate With Syndromic Thromboc...mentioning

confidence: 99%

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

Marín-Quílez

Díaz-Ajenjo

Buduo

et al. 2023

IJMS

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Protein glycosylation, including sialylation, involves complex and frequent post-translational modifications, which play a critical role in different biological processes. The conjugation of carbohydrate residues to specific molecules and receptors is critical for normal hematopoiesis, as it favors the proliferation and clearance of hematopoietic precursors. Through this mechanism, the circulating platelet count is controlled by the appropriate platelet production by megakaryocytes, and the kinetics of platelet clearance. Platelets have a half-life in blood ranging from 8 to 11 days, after which they lose the final sialic acid and are recognized by receptors in the liver and eliminated from the bloodstream. This favors the transduction of thrombopoietin, which induces megakaryopoiesis to produce new platelets. More than two hundred enzymes are responsible for proper glycosylation and sialylation. In recent years, novel disorders of glycosylation caused by molecular variants in multiple genes have been described. The phenotype of the patients with genetic alterations in GNE, SLC35A1, GALE and B4GALT is consistent with syndromic manifestations, severe inherited thrombocytopenia, and hemorrhagic complications.

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B4GALT1‐congenital disorders of glycosylation: Expansion of the phenotypic and molecular spectrum and review of the literature

Cited by 9 publications

References 20 publications

Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen

Genetic and functional evidence links a missense variant in B4GALT1 to lower LDL and fibrinogen

N-Glycoprofiling of SLC35A2-CDG: Patient with a Novel Hemizygous Variant

Inherited Thrombocytopenia Caused by Variants in Crucial Genes for Glycosylation

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