Alternative splicing in osteoclasts and Paget’s disease of boneReportar como inadecuado

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BMC Medical Genetics

, 15:98

Functional and epigenetics


BackgroundMutations in the SQSTM1-p62 gene have been reported in Paget’s disease of bone PDB, but they are not sufficient to induce the pagetic osteoclast OC phenotype. We hypothesized that specific RNA isoforms of OC-related genes may contribute to the overactivity of pagetic OCs, along with other genetic predisposing factors.

MethodsAlternative splicing AS events were studied using a PCR-based screening strategy in OC cultures from 29 patients with PDB and 26 healthy donors HD, all genotyped for the p62 mutation. Primer pairs targeting 5223 characterized AS events were used to analyze relative isoform ratios on pooled cDNA from samples of the four groups PDB, PDB, HD, HD. Of the 1056 active AS events detected in the screening analysis, 192 were re-analyzed on non-amplified cDNA from each subject of the whole cohort.

ResultsThis analysis led to the identification of six AS events significantly associated with PDB, but none with p62. The corresponding genes included LGALS8, RHOT1, CASC4, USP4, TBC1D25, and PIDD. In addition, RHOT1 and LGALS8 genes were upregulated in pagetic OCs, as were CASC4 and RHOT1 genes in the presence of p62. Finally, we showed that the proteins encoded by LGALS8, RHOT1, USP4, TBC1D25, and PIDD were expressed in human OCs.

ConclusionThis study allowed the identification of hitherto unknown players in OC biology, and our findings of a differential AS in pagetic OCs may generate new concepts in the pathogenesis of PDB.

KeywordsAlternative splicing Osteoclast Paget’s disease of bone p62-SQSTM1 Electronic supplementary materialThe online version of this article doi:10.1186-s12881-014-0098-1 contains supplementary material, which is available to authorized users.

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Autor: Roscoe Klinck - Gino Laberge - Martine Bisson - Stephen McManus - Laëtitia Michou - Jacques P Brown - Sophie Roux


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