Functional validation of novel compound heterozygous variants in B3GAT3 resulting in severe osteopenia and fractures: expanding the disease phenotype

BMC Medical Genetics

Case Report

Neil Miller¹  Shuhei Yamada²  Shuji Mizumoto²  Kazuyuki Sugahara³  Isabelle Thiffault⁴  Melanie Patterson⁴  Carol Saunders⁴  Margaret I. Gibson⁴  Sarah Soden⁵  Emily Farrow⁶  Ashley Brazil⁷  Howard Saal⁷  Katrin Hoffmann⁸  Florian Job⁸  Laurie Smith⁹  Natario Couser⁹ 

[1] Department of Medical Informatics, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA;Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Aichi, Japan;Department of Pathobiochemistry, Faculty of Pharmacy, Meijo University, 150 Yagotoyama, Tempaku-ku, 468-8503, Nagoya, Aichi, Japan;The Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Faculty of Advanced Life Science, Hokkaido University, 001-0021, Sapporo, Japan;Department of Pathology, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA;Department of Pediatrics, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA;Department of Pediatrics, Children’s Mercy Hospitals and Clinics, Kansas City, MO, USA;Center for Pediatric Genomic Medicine, Children’s Mercy Hospitals and Clinics, 2420 Pershing, Suite 100, Kansas City, MO, USA;Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, 45229, Cincinnati, OH, USA;Institute for Human Genetics and Molecular Biology, Martin Luther University Halle-Wittenberg, Magdeburger Str. 2, 06112, Halle (Saale), Germany;University of North Carolina School of Medicine, Division of Pediatric Genetics and Metabolism, Department of Pediatrics, Raleigh, NC, USA;

关键词: B3GAT3;    Glycosaminoglycan;    Glucuronyltransferase-I;    Linkeropathy;    Proteoglycan;   

DOI  :  10.1186/s12881-016-0344-9

 received in 2016-06-22, accepted in 2016-11-06,  发布年份 2016

来源: Springer

【 摘 要 】

BackgroundA 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 presentationIn 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).ConclusionsThis 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.

【 授权许可】

CC BY   
© The Author(s). 2016