Novel Splicing Mutation in B3GAT3 Associated with Short Stature, GH Deficiency, Hypoglycaemia, Developmental Delay, and Multiple Congenital Anomalies.

Samuel Bloor,Senthil Senniappan,Mohammed Didi,Dinesh Giri

doi:10.1155/2017/3941483

Samuel Bloor, Senthil Senniappan + Show 2 more

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https://doi.org/10.1155/2017/3941483

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Abstract

B3GAT3, encoding β-1,3-glucuronyltransferase 3, has an important role in proteoglycan biosynthesis. Homozygous B3GAT3 mutations have been associated with short stature, skeletal deformities, and congenital heart defects. We describe for the first time a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, recurrent ketotic hypoglycaemia, facial dysmorphism, and congenital heart defects. A female infant, born at 34 weeks' gestation to nonconsanguineous Caucasian parents with a birth weight of 1.9 kg, was noted to have cloacal abnormality, ventricular septal defect, pulmonary stenosis, and congenital sensorineural deafness. At 4 years of age, she was diagnosed with GH deficiency due to her short stature (height < 2.5 SD). MRI of the pituitary gland revealed a small anterior pituitary. She has multiple dysmorphic features: anteverted nares, small upturned nose, hypertelorism, slight frontal bossing, short proximal bones, hypermobile joints, and downslanting palpebral fissures. Whole exome sequencing (WES) was performed on the genomic DNA from the patient and biological mother. A heterozygous mutation in B3GAT3 (c.888+262T>G) in the invariant “GT” splice donor site was identified. This variant is considered to be pathogenic as it decreases the splicing efficiency in the mRNA.

Highlights

Proteoglycans are an influential component of the extracellular matrix, orchestrating the cell-cell and cell-matrix interactions [1]
We describe, for the first time, a novel heterozygous splice site mutation in B3GAT3 contributing to severe short stature, growth hormone (GH) deficiency, facial dysmorphisms, and congenital heart defects amongst other symptoms
Of the 203 genetic variants that Ingenuity Variant Analysis (IVA) filtered as likely to be pathogenic, genes such as COL24A1, PLXND1, TECRL, EBF2, ABLIM1, PRDM10, and POSTN were filtered out as they did not segregate with the patient phenotype following a detailed review of the biological information available from the current literature [8,9,10,11,12,13,14]

Summary

Introduction

Proteoglycans are an influential component of the extracellular matrix, orchestrating the cell-cell and cell-matrix interactions [1]. Proteoglycans are produced through the secretory pathway in the endoplasmic reticulum followed by the construction of the glycosaminoglycan (GAG) side chain within the Golgi complex. Β-1,3-Glucuronyltransferase 3 (GlcAT-I), encoded by B3GAT3, is located on chromosome 11q12.3 [4] and consists of 335 amino acids with one N-linked glycan chain [5]. GlcATI is a glucuronyltransferase involved in the biosynthesis of GAG-protein linkers for proteoglycans. GlcATI contributes to the addition of the terminal four saccharides, xylose-galactose-galactose-glucuronic acid, its presence in the cis-Golgi [6]. The addition of this tetrasaccharide provides an external face for binding by extracellular signals

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