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Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas.
PLoS One. 2012; 7(3):e33251.Plos

Abstract

Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing, and 2/148 (1%) leiomyomas exhibited heterozygous deletions/insertion-deletions spanning the intron 1-exon 2 boundary which affected the splice acceptor site. Mutations were not detected in MED12 in normal myometrial tissue. MED12 mutations were equally distributed among karyotypically normal and abnormal uterine leiomyomas and were identified in leiomyomas from both black and white American women. Our studies show an association between MED12 mutations and leiomyomas in ethnically and racially diverse American women.

Authors+Show Affiliations

Department of Obstetrics, Gynecology and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh, Pittsburgh, Pennsylvania, United States of America.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

22428002

Citation

McGuire, Megan M., et al. "Whole Exome Sequencing in a Random Sample of North American Women With Leiomyomas Identifies MED12 Mutations in Majority of Uterine Leiomyomas." PloS One, vol. 7, no. 3, 2012, pp. e33251.
McGuire MM, Yatsenko A, Hoffner L, et al. Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PLoS ONE. 2012;7(3):e33251.
McGuire, M. M., Yatsenko, A., Hoffner, L., Jones, M., Surti, U., & Rajkovic, A. (2012). Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. PloS One, 7(3), e33251. https://doi.org/10.1371/journal.pone.0033251
McGuire MM, et al. Whole Exome Sequencing in a Random Sample of North American Women With Leiomyomas Identifies MED12 Mutations in Majority of Uterine Leiomyomas. PLoS ONE. 2012;7(3):e33251. PubMed PMID: 22428002.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Whole exome sequencing in a random sample of North American women with leiomyomas identifies MED12 mutations in majority of uterine leiomyomas. AU - McGuire,Megan M, AU - Yatsenko,Alexander, AU - Hoffner,Lori, AU - Jones,Mirka, AU - Surti,Urvashi, AU - Rajkovic,Aleksandar, Y1 - 2012/03/12/ PY - 2012/01/12/received PY - 2012/02/11/accepted PY - 2012/3/20/entrez PY - 2012/3/20/pubmed PY - 2012/8/21/medline SP - e33251 EP - e33251 JF - PloS one JO - PLoS ONE VL - 7 IS - 3 N2 - Uterine leiomyomas (uterine fibroids) arise from smooth muscle tissue in the majority of women by age 45. It is common for these clonal tumors to develop from multiple locations within the uterus, leading to a variety of symptoms such as pelvic pain, abnormal uterine bleeding, and infertility. We performed whole exome sequencing on genomic DNA from five pairs of leiomyomas and corresponding normal myometrium to determine genetic variations unique to leiomyomas. Whole exome sequencing revealed that the gene encoding transcription factor MED12 (Mediator complex subunit 12) harbored heterozygous missense mutations caused by single nucleotide variants in highly conserved codon 44 of exon 2 in two of five leiomyomas. Sanger re-sequencing of MED12 among these five leiomyomas confirmed the two single nucleotide variants and detected a 42 base-pair deletion within exon 2 of MED12 in a third leiomyoma. MED12 was sequenced in an additional 143 leiomyomas and 73 normal myometrial tissues. Overall, MED12 was mutated in 100/148 (67%) of the genotyped leiomyomas: 79/148 (53%) leiomyomas exhibited heterozygous missense single nucleotide variants, 17/148 (11%) leiomyomas exhibited heterozygous in-frame deletions/insertion-deletions, 2/148 (1%) leiomyomas exhibited intronic heterozygous single nucleotide variants affecting splicing, and 2/148 (1%) leiomyomas exhibited heterozygous deletions/insertion-deletions spanning the intron 1-exon 2 boundary which affected the splice acceptor site. Mutations were not detected in MED12 in normal myometrial tissue. MED12 mutations were equally distributed among karyotypically normal and abnormal uterine leiomyomas and were identified in leiomyomas from both black and white American women. Our studies show an association between MED12 mutations and leiomyomas in ethnically and racially diverse American women. SN - 1932-6203 UR - https://www.unboundmedicine.com/medline/citation/22428002/Whole_exome_sequencing_in_a_random_sample_of_North_American_women_with_leiomyomas_identifies_MED12_mutations_in_majority_of_uterine_leiomyomas_ L2 - http://dx.plos.org/10.1371/journal.pone.0033251 DB - PRIME DP - Unbound Medicine ER -