MED12 Mutation in Two Families with X-Linked Ohdo Syndrome

X-linked intellectual deficiency (XLID) is a widely heterogeneous group of genetic disorders that involves more than 100 genes. The mediator of RNA polymerase II subunit 12 (MED12) is involved in the regulation of the majority of RNA polymerase II-dependent genes and has been shown to cause several forms of XLID, including Opitz-Kaveggia syndrome also known as FG syndrome (MIM #305450), Lujan-Fryns syndrome (MIM #309520) and the X-linked Ohdo syndrome (MIM #300895). Here, we report on two first cousins with X-linked Ohdo syndrome with a missense mutation in MED12 gene, identified through whole exome sequencing. The probands had facial features typical of X-linked Ohdo syndrome, including blepharophimosis, ptosis, a round face with a characteristic nose and a narrow mouth. Nextera DNA Exome kit (Illumina Inc., San Diego, CA, USA) was used for exome capture. The variant identified was a c.887G > A substitution in exon 7 of the MED12 gene leading to the substitution of a glutamine for a highly conserved arginine (p. Arg296Gln). Although the variant described has been previously reported in the literature, our study contributes to the expanding phenotypic spectrum of MED12-related disorders and above all, it demonstrates the phenotypic variability among different affected patients despite harboring identical mutations.

Pathogenomics of Uterine Fibroids Development

We review recent studies dealing with the molecular genetics and basic results of omics analysis of uterine leiomyoma (LM)—a common benign muscle tumor of the uterus. Whole genome studies of LM resulted in the discovery of many new gene nets and biological pathways, including its origin, transcriptomic, and epigenetic profiles, as well as the impact of the inter-cell matrix in LM growth and involvement of microRNA in its regulation. New data on somatic cell mutations ultimately involved in the origin, distribution and growth of LM are reviewed. Putative identification of LM progenitor SC (stem cells) giving rise to maternal fibroid nodes and junctional zones provide a new clue for hypotheses on the pathogenomics of LM. The reviewed data are consistent with at least two different but probably intimately interacted molecular mechanisms of LM. One of them (the genetic hypothesis) is focused primarily on the MED12 gene mutations and suggests its onset in the side population of embryonic myoblasts of the female reproductive system, which later gave rise to multiple small and medium fibroids. The single and usually large-size fibroids are induced by predominantly epigenetic disorders in LM SC, provoked by enhanced expression of the HMGA2 gene caused by its hypomethylation and epigenetic deregulation enhanced by hypoxia, muscle tension, or chromosome instability/aberrations. The pathogenomics of both genetic and epigenetic programs of LM with many peculiarities at the beginning later became rather similar and partly overlapped due to the proximity of their gene nets and epigenetic landscape. Pathogenomic studies of LM open ways for elaboration of novel strategies of prevention and treatment of this common disease.

Extracellular Matrix (ECM) Activates β-catenin Signaling in Uterine Fibroids

κΩΨ¥–€™±≈‰ greater than > less than Recent studies showed that genetic aberrations in the MED12 gene, probably through the canonical WNT/β-catenin pathway, lead to the pathogenesis of uterine fibroids. However, a comprehensive analysis of the WNT pathway in MED12-mutated and MED12-wild type fibroids has not been performed. The objective of this study was to determine the status of the WNT pathway in human fibroids. We performed Sanger sequencing to define the MED12 mutational status of fibroids and normal myometrium samples. qPCR arrays were carried out to determine the status of the WNT signaling pathway in MED12-mutated and MED12-wild type fibroids. Liquid chromatography-mass spectrometry (LC-MS), western blotting, and immunohistochemistry were used to monitor the expression of β-catenin. We showed that β-catenin expression was increased in fibroids compared to the adjacent myometrium samples. However, β-catenin expression showed no correlation with MED12 mutation status. Of all the WNT signaling components, WNT inhibitors showed the greatest differences in expression between fibroids and controls. WIF1, a WNT inhibitor, was identified as the most significantly upregulated gene in fibroids. We cultured primary fibroid cells on hydrogels of known stiffness to decipher the influence of biomechanical cues on β-catenin expression and revealed increased levels of β-catenin when cells were cultured on a stiffer surface. In conclusion, our data showed that β-catenin expression in fibroids occurs independently of MED12 mutations. Biomechanical changes upregulate β-catenin expression in fibroids, providing an attractive avenue for developing new treatments for this disease.

Uterine Fibroids: Bridging Genomic Defects and Chronic Inflammation

Uterine fibroids (UF; aka leiomyoma, myomas) are the most common benign tumors of female reproductive tract. They are highly prevalent, with 70 to 80% of women burdened by the end of their reproductive years. Fibroids are a leading cause of pelvic pain, abnormal vaginal bleeding, pelvic bulk symptoms, miscarriage, and infertility. They are the leading indication for hysterectomy, and costs exceed 34 billion dollars annually in the United States alone. Recently, somatic mutations in exons 1 and 2 of Med12 gene emerged as common UF driver mutations. Unfortunately, the detailed etiology of UF is not fully realized. Particularly, very little is known about possible dysregulation of inflammatory and immune processes and their possible contribution to UF pathogenesis. The notion on possible impact of altered estrogen and progesterone signaling in UF on inflammatory responses and DNA repair machinery that can conceivably lead to tumor-specific somatic mutation is indeed an intriguing concept which has some foundation in available observation in other hormonally responsive tissues. This review highlights and summarizes our current knowledge on the convergence of such pathways and their relevance for UF pathogenesis.