Expanded Somatic Mutation Spectrum of MED12 Gene in Uterine Leiomyomas of Saudi Arabian Women

Abstract

MED12, a subunit of mediator complex genes is known to harbor genetic mutations, (mostly in exon 2), causal to the genesis of uterine leiomyomas among Caucasian, African American, and Asian women. However, the precise relationship between genetic mutations vs. protein or disease phenotype is not well-explained. Therefore, we sought to replicate the MED12 mutation frequency in leiomyomas of Saudi Arabian women, who represents ethnically and culturally distinct population. We performed molecular screening of MED12 gene (in 308 chromosomes belonging to 154 uterine biopsies), analyzed the genotype-disease phenotype correlations and determined the biophysical characteristics of mutated protein through diverse computational approaches. We discovered that >44% (34/77) leiomyomas of Arab women carry a spectrum of MED12 mutations (30 missense, 1 splice site, and 3 indels). In addition to known codon 44, we observed novel somatic mutations in codons 36, 38, and 55. Most genetically mutated tumors (27/30; 90%) demonstrated only one type of genetic change, highlighting that even single allele change in MED12 can have profound impact in transforming the normal uterine myometrium to leiomyomas. An interesting inverse correlation between tumor size and LH is observed when tumor is positive to MED12 mutation (p < 0.05). Our computational investigations suggest that amino acid substitution mutations in exon-2 region of MED12 might contribute to potential alterations in phenotype as well as the stability of MED12 protein. Our study, being the first one from Arab world, confirms the previous findings that somatic MED12 mutations are critical to development and progression of uterine leiomyomas irrespective of the ethnic background. We recommend that mutation screening, particularly codon 44 of MED12 can assist in molecular diagnostics of uterine leiomyomas in majority of the patients.

Whole exome sequencing identifies rare biallelic ALMS1 missense and stop gain mutations in familial Alström syndrome patients

“…Subsequently, PCR amplification reaction and agarose gel (1%) electrophoresis methods were executed to amplify and analyze the amplicon band sizes. The PCR products were purified, cycle sequencedin ABI-Prism 3700 Genetic Analyzer using Dideoxy nucleotide sequencing method (Ajabnoor et al, 2018). Alignment and annotation of nucleotide sequence mismatches were carried out using BioEdit (http://www.mbio.ncsu.edu/) program.…”

Multiple Mutations in Exon-2 of Med-12 Identified in Uterine Leiomyomata

“…Published evidence indicates that MED-12 somatic sequence variants contribute to the etiology of 70–85% of UL. Exon-2 is considered as the hotspot of this gene as reported from UL studies of different ethnic groups like North American ( 25 ), South African ( 26 ), Finnish ( 27 ), and Saudi Arabian ( 28 ). The total somatic mutations of MED-12 were observed in 41% of the UL samples studied.…”

The role of mediator subunit 12 in tumorigenesis and cancer therapeutics (Review)

“…The MED12 mutation patterns of both phyllodes tumors and fibroadenomas are very similar, with missense and deletion-insertion mutations occurring mainly in exon 2 (and a small number in exon 1), with codon 44 being the most commonly mutated (86%) ( 15 , 38 , 44 ) ( Table I ). Codons 36 and 43 are also affected, but at a much less frequent rate ( 16 ). Similar to uterine leiomyomas and phyllodes tumors, exon 2 mutations disrupt CDK8 kinase activity ( 44 ).…”