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Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma.
Mol Hum Reprod. 2014 Oct; 20(10):1009-15.MH

Abstract

Uterine leiomyoma (UL), the most common benign tumour found in females, is associated with many recurrent genetic aberrations, such as translocations, interstitial deletions and specific germline mutations. Among these, mutations affecting exon 2 of the mediator complex subunit 12 (MED12) gene are commonly detected in the majority of ULs. Mutational analysis of the MED12 gene, performed on 36 UL samples, revealed that 12 leiomyomas (33.4%) exhibited heterozygous missense mutations in codon 44 of exon 2 of the MED12 gene, four leiomyomas (11.1%) showed internal in-frame deletions, and two leiomyomas (5.5%) exhibited deletions involving intron 1-exon 2 junction, which caused a predicted loss of the splice acceptor. No mutations were detected in uterine myometrium (UM) and pseudocapsule (PC) samples, including those from women with a MED12 mutation in UL. These data showed that the PC is a healthy tissue that surrounds the UL to maintain UM integrity. Analysis of insulin-like growth factor 2 (IGF-2) and collagen type IV alpha 2 (COL4A2) mRNA expression levels in the same set of ULs revealed that only those with MED12 missense mutations expressed significantly higher levels of IGF-2 mRNA. In contrast, MED12 gene status does not appear to affect mRNA expression levels of the COL4A2 gene. On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation. The occurrence of IGF-2 overexpression could be therapeutically targeted for the non-surgical treatment of leiomyomas.

Authors+Show Affiliations

Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy.Division of Experimental Endoscopic Surgery, Imaging, Minimally Invasive Therapy and Technology, Department of Gynecology and Obstetrics, Vito Fazzi Hospital, Lecce 73100, Italy.Department of Obstetrics and Gynecology, Santa Maria Hospital, Bari 70100, Italy.Department of Biological and Environmental Sciences and Technologies, University of Salento, Lecce 73100, Italy sara.massari@unisalento.it.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25015674

Citation

Di Tommaso, S, et al. "Missense Mutations in Exon 2 of the MED12 Gene Are Involved in IGF-2 Overexpression in Uterine Leiomyoma." Molecular Human Reproduction, vol. 20, no. 10, 2014, pp. 1009-15.
Di Tommaso S, Tinelli A, Malvasi A, et al. Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma. Mol Hum Reprod. 2014;20(10):1009-15.
Di Tommaso, S., Tinelli, A., Malvasi, A., & Massari, S. (2014). Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma. Molecular Human Reproduction, 20(10), 1009-15. https://doi.org/10.1093/molehr/gau055
Di Tommaso S, et al. Missense Mutations in Exon 2 of the MED12 Gene Are Involved in IGF-2 Overexpression in Uterine Leiomyoma. Mol Hum Reprod. 2014;20(10):1009-15. PubMed PMID: 25015674.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Missense mutations in exon 2 of the MED12 gene are involved in IGF-2 overexpression in uterine leiomyoma. AU - Di Tommaso,S, AU - Tinelli,A, AU - Malvasi,A, AU - Massari,S, Y1 - 2014/07/11/ PY - 2014/7/13/entrez PY - 2014/7/13/pubmed PY - 2015/6/10/medline KW - COL4A2 gene KW - IGF-2 gene KW - MED12 gene KW - pseudocapsule KW - uterine leiomyoma SP - 1009 EP - 15 JF - Molecular human reproduction JO - Mol. Hum. Reprod. VL - 20 IS - 10 N2 - Uterine leiomyoma (UL), the most common benign tumour found in females, is associated with many recurrent genetic aberrations, such as translocations, interstitial deletions and specific germline mutations. Among these, mutations affecting exon 2 of the mediator complex subunit 12 (MED12) gene are commonly detected in the majority of ULs. Mutational analysis of the MED12 gene, performed on 36 UL samples, revealed that 12 leiomyomas (33.4%) exhibited heterozygous missense mutations in codon 44 of exon 2 of the MED12 gene, four leiomyomas (11.1%) showed internal in-frame deletions, and two leiomyomas (5.5%) exhibited deletions involving intron 1-exon 2 junction, which caused a predicted loss of the splice acceptor. No mutations were detected in uterine myometrium (UM) and pseudocapsule (PC) samples, including those from women with a MED12 mutation in UL. These data showed that the PC is a healthy tissue that surrounds the UL to maintain UM integrity. Analysis of insulin-like growth factor 2 (IGF-2) and collagen type IV alpha 2 (COL4A2) mRNA expression levels in the same set of ULs revealed that only those with MED12 missense mutations expressed significantly higher levels of IGF-2 mRNA. In contrast, MED12 gene status does not appear to affect mRNA expression levels of the COL4A2 gene. On the basis of this finding, we suggest that the MED12 status stratifies the ULs into two mutually exclusive pathways of leiomyoma genesis, one with IGF-2 overexpression and the other with no IGF-2 activation. The occurrence of IGF-2 overexpression could be therapeutically targeted for the non-surgical treatment of leiomyomas. SN - 1460-2407 UR - https://www.unboundmedicine.com/medline/citation/25015674/Missense_mutations_in_exon_2_of_the_MED12_gene_are_involved_in_IGF_2_overexpression_in_uterine_leiomyoma_ L2 - https://academic.oup.com/molehr/article-lookup/doi/10.1093/molehr/gau055 DB - PRIME DP - Unbound Medicine ER -