A pain in the back


Pain in the lower back can be caused by a variety of factors including overuse injury, aging, and arthritis. A major source of back pain is lumbar disc degeneration (LDD), which is characterized by loss of the fluid and glycoprotein matrix within intervertebral discs. Early-onset of LDD is observed among members of the same family, indicating that there is some genetic component underlying LDD development; however, genetic risk factors for this disease are poorly understood. You-Qiang Song, Tatsuki Karasugi, and colleagues identified mutations that resulted in decreased expression of the gene encoding sulfite carbohydrate sulfotransferase 3 (CHST3) that were associated with LDD in a large sample of patients. One common mutation mapped to the 3’ untranslated region of the CHST3 gene, which contains a miR-513a-5p binding site. The authors determined that LDD-associated mutations in the 3’ UTR enhanced miR-513a-5p binding, resulting in decreased CHST3 expression. Furthermore, patients with early-onset LDD had decreased CHST3 mRNA levels in their intervertebral discs. This study indicates that LDD development can be predicted by decreased CHST3 expression. The above MRI depicts a normal individual (left) and patients of parents with known CHST3 mutations (right images). Disc degeneration with reduced nucleus pulposus intensity (pink arrows), abnormal end-plate (yellow arrows) consistent with Schmorl’s nodes, and irregular darkened NP signals (orange arrows) were observed.

Published October 8, 2013, by Corinne Williams

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Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant
You-Qiang Song, … , Shiro Ikegawa, Danny Chan
You-Qiang Song, … , Shiro Ikegawa, Danny Chan
Published October 8, 2013
Citation Information: J Clin Invest. 2013;123(11):4909-4917. https://doi.org/10.1172/JCI69277.
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Lumbar disc degeneration is linked to a carbohydrate sulfotransferase 3 variant

Abstract

Lumbar disc degeneration (LDD) is associated with both genetic and environmental factors and affects many people worldwide. A hallmark of LDD is loss of proteoglycan and water content in the nucleus pulposus of intervertebral discs. While some genetic determinants have been reported, the etiology of LDD is largely unknown. Here we report the findings from linkage and association studies on a total of 32,642 subjects consisting of 4,043 LDD cases and 28,599 control subjects. We identified carbohydrate sulfotransferase 3 (CHST3), an enzyme that catalyzes proteoglycan sulfation, as a susceptibility gene for LDD. The strongest genome-wide linkage peak encompassed CHST3 from a Southern Chinese family–based data set, while a genome-wide association was observed at rs4148941 in the gene in a meta-analysis using multiethnic population cohorts. rs4148941 lies within a potential microRNA-513a-5p (miR-513a-5p) binding site. Interaction between miR-513a-5p and mRNA transcribed from the susceptibility allele (A allele) of rs4148941 was enhanced in vitro compared with transcripts from other alleles. Additionally, expression of CHST3 mRNA was significantly reduced in the intervertebral disc cells of human subjects carrying the A allele of rs4148941. Together, our data provide new insights into the etiology of LDD, implicating an interplay between genetic risk factors and miRNA.

Authors

You-Qiang Song, Tatsuki Karasugi, Kenneth M.C. Cheung, Kazuhiro Chiba, Daniel W.H. Ho, Atsushi Miyake, Patrick Y.P. Kao, Kit Ling Sze, Anita Yee, Atsushi Takahashi, Yoshiharu Kawaguchi, Yasuo Mikami, Morio Matsumoto, Daisuke Togawa, Masahiro Kanayama, Dongquan Shi, Jin Dai, Qing Jiang, Chengai Wu, Wei Tian, Na Wang, John C.Y. Leong, Keith D.K. Luk, Shea-ping Yip, Stacey S. Cherny, Junwen Wang, Stefan Mundlos, Anthi Kelempisioti, Pasi J. Eskola, Minna Männikkö, Pirkka Mäkelä, Jaro Karppinen, Marjo-Riitta Järvelin, Paul F. O’Reilly, Michiaki Kubo, Tomoatsu Kimura, Toshikazu Kubo, Yoshiaki Toyama, Hiroshi Mizuta, Kathryn S.E. Cheah, Tatsuhiko Tsunoda, Pak-Chung Sham, Shiro Ikegawa, Danny Chan

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