Document Type
Article
Publication Date
11-21-2016
Identifier
PMCID: PMC5117547 DOI: 10.1186/s12881-016-0344-9
Abstract
BACKGROUND: A new disease class of syndromes, described as linkeropathies, which are derived from defects in the glycosaminoglycan-linker region as well as glycosaminoglycan-side chains of proteoglycans is increasingly being recognized as a cause of human disease. Proteoglycans are an essential component of the extracellular matrix. Defects in the enzymatic process of proteoglycan synthesis broadly occur due to the incorrect addition of side chains. Previously, homozygous missense variants within the B3GAT3 gene encoding beta 1,3 glucuronyltransferase 3(GlcAT-I) responsible for the biosynthesis of glycosaminoglycans have been described in 7 individuals.
CASE PRESENTATION: In this study, a 4-year-old patient with a severe phenotype of osteoporosis, hypotonia, joint laxity, fractures, scoliosis, biscuspid aortic valve and myopia was referred for next generation sequencing after extensive negative clinical testing. Whole exome sequencing was performed on the proband and his unaffected parents to identify the molecular basis of his disease. Sequencing revealed compound heterozygous variants in B3GAT3: c.1A > G (p.Met1?) and c.671 T > A (p.L224Q). Clinical and in vitro functional studies were then completed to verify the pathogenicity of the genotype and further characterize the functional basis of the patient's disease demonstrating the patient had a decrease both in the protein level of B3GAT3 and in the glucuronyltransferase activity when compared to control samples. Independent in vitro assessment of each variant confirmed the B3GAT3: c.1A > G (p.Met1?) variant is functionally null and the c.671 T > A (p.L224Q) missense variant has significantly reduced glucuronyltransferase activity (~3% of control).
CONCLUSIONS: This is the first report of a patient with compound heterozygosity for a null variant in trans with a missense in B3GAT3 resulting in a severe phenotype, expanding both the genotypic and phenotypic spectrum of B3GAT3-related disease.
Journal Title
BMC medical genetics [electronic resource]
Volume
17
Issue
1
First Page
86
Last Page
86
MeSH Keywords
Bone Diseases, Metabolic; Child, Preschool; DNA; Fractures, Bone; Genetic Variation; Genotype; Glucuronosyltransferase; Heterozygote; High-Throughput Nucleotide Sequencing; Humans; Male; Mutation, Missense; Pedigree; Phenotype; Recombinant Proteins
Keywords
B3GAT3; Glucuronyltransferase-I; Glycosaminoglycan; Linkeropathy; Proteoglycan
Recommended Citation
Job F, Mizumoto S, Smith L, et al. Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype. BMC Med Genet. 2016;17(1):86. Published 2016 Nov 21. doi:10.1186/s12881-016-0344-9
Included in
Congenital, Hereditary, and Neonatal Diseases and Abnormalities Commons, Medical Genetics Commons, Musculoskeletal Diseases Commons, Pathology Commons, Pediatrics Commons
Comments
This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Publisher's Link: https://bmcmedgenet.biomedcentral.com/articles/10.1186/s12881-016-0344-9