A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate

Xian, Caixia; Zhu, Mingwei; Nong, Tianying; Li, Yiqiang; Xie, Xing-Mei; Li, Xia; Li, Jiangui; Li, Jingchun; Wu, Jianping; Shi, Weizhe; Wei, Ping; Xu, Hongyan; Tang, Yaping

doi:10.1590/1678-4685-gmb-2020-0334

Cited by 7 publications

(7 citation statements)

References 26 publications

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“…Genomic DNA was extracted from the venous blood leucocytes of every test person utilizing a genomic DNA extraction kit (Promega, USA). Whole-exome sequencing (WES) and bioinformatical analysis in five affected family members (I-1, II-1, II-6, III-2 and III-4, Figure 1A ) and four unaffected family members (I-2, II-2, II-5 and III-1, Figure 1A ) were performed as described previously ( Di et al , 2020 ; Qiao et al , 2020 ; Linhares et al , 2021 ; Wang et al , 2021 ; Xian et al , 2021 ). In brief, each exome library was constructed using 5 μg of genomic DNA from a study subject, enriched by ligation-mediated polymerase chain reaction (PCR) and captured with the SureSelect Human All Exon V6 Kit (Agilent Technologies, USA).…”

Section: Methodsmentioning

confidence: 99%

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

Zhang

Guo

et al. 2022

Genet. Mol. Biol.

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Atrial fibrillation (AF) represents the most common type of sustained cardiac arrhythmia in humans and confers a significantly increased risk for thromboembolic stroke, congestive heart failure and premature death. Aggregating evidence emphasizes the predominant genetic defects underpinning AF and an increasing number of deleterious variations in more than 50 genes have been involved in the pathogenesis of AF. Nevertheless, the genetic basis underlying AF remains incompletely understood. In the current research, by whole-exome sequencing and Sanger sequencing analysis in a family with autosomal-dominant AF and congenital patent ductus arteriosus (PDA), a novel heterozygous variation in the PRRX1 gene encoding a homeobox transcription factor critical for cardiovascular development, NM_022716.4:c.373G>T;p.(Glu125 * ), was identified to be in co-segregation with AF and PDA in the whole family. The truncating variation was not detected in 306 unrelated healthy individuals employed as controls. Quantitative biological measurements with a reporter gene analysis system revealed that the Glu125 * -mutant PRRX1 protein failed to transactivate its downstream target genes SHOX2 and ISL1 , two genes that have been causally linked to AF. Conclusively, the present study firstly links PRRX1 loss-of-function variation to AF and PDA, suggesting that AF and PDA share a common abnormal developmental basis in a proportion of cases.

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Section: Methodsmentioning

confidence: 99%

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

Zhang

Guo

et al. 2022

Genet. Mol. Biol.

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“…Genomic DNA (gDNA) was extracted from the peripheral blood of all subjects with a Blood DNA Kit (Omega, USA) according to the manufacturer’s instructions. Whole exome sequencing (WES) was performed at the Novogene (Beijing, China) as previously described ( Xian et al., 2021 ).…”

Section: Methodsmentioning

confidence: 99%

Identification of a novel TBX5 mutation in a Chinese family with rare symptoms of Holt–Oram syndrome

Shi²,

Ding³

et al. 2022

Heliyon

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“…Disorders identified in the genes for HS biotransformation are rare in both HSbiosynthesis and HS degradation. Exostosis is a rare disease that is caused by dominant mutation of EXT1/EXT2 enzymes in humans [21,141]. Disorders caused by Nand O-sulfotransferases, C5-epimerase, and 6-O-sulfatases have not been described in humans.…”

Section: Diseases In Humansmentioning

confidence: 99%

Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation

Mashima¹,

Okuyama²,

Ohira³

2022

IJMS

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Heparan sulfate (HS) is a type of glycosaminoglycan that plays a key role in a variety of biological functions in neurology, skeletal development, immunology, and tumor metastasis. Biosynthesis of HS is initiated by a link of xylose to Ser residue of HS proteoglycans, followed by the formation of a linker tetrasaccharide. Then, an extension reaction of HS disaccharide occurs through polymerization of many repetitive units consisting of iduronic acid and N-acetylglucosamine. Subsequently, several modification reactions take place to complete the maturation of HS. The sulfation positions of N-, 2-O-, 6-O-, and 3-O- are all mediated by specific enzymes that may have multiple isozymes. C5-epimerization is facilitated by the epimerase enzyme that converts glucuronic acid to iduronic acid. Once these enzymatic reactions have been completed, the desulfation reaction further modifies HS. Apart from HS biosynthesis, the degradation of HS is largely mediated by the lysosome, an intracellular organelle with acidic pH. Mucopolysaccharidosis is a genetic disorder characterized by an accumulation of glycosaminoglycans in the body associated with neuronal, skeletal, and visceral disorders. Genetically modified animal models have significantly contributed to the understanding of the in vivo role of these enzymes. Their role and potential link to diseases are also discussed.

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A novel mutation in ext2 caused hereditary multiple exostoses through reducing the synthesis of heparan sulfate

Cited by 7 publications

References 26 publications

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

A novel PRRX1 loss-of-function variation contributing to familial atrial fibrillation and congenital patent ductus arteriosus

Identification of a novel TBX5 mutation in a Chinese family with rare symptoms of Holt–Oram syndrome

Physiology and Pathophysiology of Heparan Sulfate in Animal Models: Its Biosynthesis and Degradation

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