A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Risheg, Hiba; Graham, John M.; Clark, Robin D.; Rogers, R. Curtis; Opitz, John M.; Moeschler, John B.; Peiffer, Andreas; May, Melanie; Joseph, Sumy; Jones, Julie R.; Stevenson, Roger E.; Schwartz, Charles E.; Friez, Michael J.

doi:10.1038/ng1992

Cited by 175 publications

(163 citation statements)

References 15 publications

Supporting

Mentioning

159

Contrasting

Order By: Relevance

“…Germline mutations affecting MED12 exons 21 and 22-which encode a leucine-and serine-rich domain-cause the X-linked recessive hereditary syndromes Opitz-Kaveggia (OMIM 305450) and Lujan-Fryns (OMIM 309520). [25][26][27] These disorders are characterized by overlapping phenotypes, including mental retardation and dysmorphic features, but are not associated with tumor predisposition; 28 however, missense mutations of the same MED12 leucine-and serine-rich domain are found in 5% of prostate adenocarcinomas. 29 The different MED12 mutation hotspots in smooth muscle neoplasia versus prostate cancer are consistent with multifaceted MED12 roles in various cell lineages and with the complex biology of the Mediator complex.…”

Section: Discussionmentioning

confidence: 99%

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

et al. 2013

View full text Add to dashboard Cite

Leiomyoma and leiomyosarcoma share morphological features and smooth muscle differentiation, and both arise most frequently within the uterine corpus of middle-aged women. However, they are considered biologically unrelated tumors due to their disparate clinical, cytogenetic, and molecular features. MED12, the mediator complex subunit 12 gene, has been recently implicated as an oncogene in as many as 70% of sporadic uterine leiomyoma. In the present study, we show MED12 hotspot exon 2 mutations in extrauterine leiomyoma (3 of 19 cases) and in leiomyosarcoma (3 of 13 uterine cases). We also show that MED12 mutations are found in both primary and metastatic leiomyosarcoma. Immunoblotting studies demonstrated MED12 protein expression in 100% of leiomyomas (13) Keywords: fibroid; leiomyoma; leiomyosarcoma; MED12; oncogene; smooth muscle tumor; uterus Seventy percent of women in the general population develop uterine leiomyomas, 1 and B25% of women experience substantial symptoms from these tumors, leading to over 200 000 hysterectomies annually in the United States. 1 By contrast, uterine leiomyosarcomas are infrequent, with an estimated incidence of 0.64 per 100 000 women. Nonetheless, uterine leiomyosarcomas are among the most common sarcomas, accounting for 2-5% of tumors of the uterine body. [2][3][4] There is substantial morphological overlap between leiomyoma and low-grade spindle cell leiomyosarcoma, and diagnostic distinction between these entities relies on histopathological criteria, including nuclear atypia, mitotic activity, and tumor cell necrosis. 5 Morphological variants and unusual features can further complicate the diagnosis between leiomyoma versus leiomyosarcoma, as in smooth muscle tumors of uncertain malignant potential that cannot be unequivocally classified as benign or malignant. 6 Recently, somatic mutations affecting MED12 (the mediator complex subunit 12 gene) were discovered in B70% of sporadic uterine leiomyoma. 7,8 Mediator is a modular protein complex of 25 subunits that regulates RNA polymerase II-mediated transcription, thereby orchestrating cell development and survival in cooperation with CDK8. 9,10 MED12 is located on chromosome sub-band Xq13.1 and is composed of 45 exons, although all MED12 mutations thus far described in uterine leiomyoma have affected exon 2 exclusively, with mutation hotspots in codons 36-44.In the present study, we analyzed leiomyomas and leiomyosarcomas of various biological behaviors and anatomical locations to better determine the relevance of MED12 exon 2 mutations across a broad spectrum of smooth muscle neoplasia. In these studies, we also determined whether MED12 expression is dysregulated in smooth muscle neoplasia compared with a normal myometrium control. These studies demonstrate that MED12 mutations are the first known oncogenic mechanism shared by uterine and extrauterine leiomyoma and uterine leiomyosarcoma.

show abstract

Section: Discussionmentioning

confidence: 99%

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

et al. 2013

View full text Add to dashboard Cite

show abstract

“…Missense mutations of MED12 are associated with X-linked genetic syndromes [103][104][105]. Somatic mutations have been described in many solid tumors, including, hormone-associated cancers (prostate and adrenocortical carcinoma) [106,107], breast [108], uterine tumors [109].…”

Section: Med12 Mutationsmentioning

confidence: 99%

Chronic lymphocytic leukemia: Time to go past genomics?

2016

View full text Add to dashboard Cite

Recent advances in massively parallel sequencing technologies have provided a detailed picture of the mutational landscape in CLL and underscored the vast degree of interpatient and intratumor heterogeneities. These studies have led to the characterization of novel putative driver genes and recurrently affected biological pathways, and to the modeling of CLL clonal evolution. We herein review selected aspects including recent advances in the biology of CLL and present cellular and biological processes involved in the development of CLL and potentially other mature B-cell lymphoproliferative neoplasms.

show abstract

“…1 From the family of Mediator complex, MED12 is known to be involved in the etiology of Opitz-Kaveggia syndrome (FG syndrome, MIM no. 305450) 4 and Lujan-Fryns syndrome (MIM no. 309520), 5 X-linked disorders characterized by ID, hypotonia and minor anomalies such as macrocephaly or high forehead and rarely congenital heart defects.…”

Section: Introductionmentioning

confidence: 99%

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Asadollahi

Oneda

Sheth³

et al. 2013

Eur J Hum Genet

View full text Add to dashboard Cite

A chromosomal balanced translocation disrupting the MED13L (Mediator complex subunit13-like) gene, encoding a subunit of the Mediator complex, was previously associated with transposition of the great arteries (TGA) and intellectual disability (ID), and led to the identification of missense mutations in three patients with isolated TGA. Recently, a homozygous missense mutation in MED13L was found in two siblings with non-syndromic ID from a consanguineous family. Here, we describe for the first time, three patients with copy number changes affecting MED13L and delineate a recognizable MED13L haploinsufficiency syndrome. Using high resolution molecular karyotyping, we identified two intragenic de novo frameshift deletions, likely resulting in haploinsufficiency, in two patients with a similar phenotype of hypotonia, moderate ID, conotruncal heart defect and facial anomalies. In both, Sanger sequencing of MED13L did not reveal any pathogenic mutation and exome sequencing in one patient showed no evidence for a non-allelic second hit. A further patient with hypotonia, learning difficulties and perimembranous VSD showed a 1 Mb de novo triplication in 12q24.2, including MED13L and MAP1LC3B2. Our findings show that MED13L haploinsufficiency in contrast to the previously observed missense mutations cause a distinct syndromic phenotype. Additionally, a MED13L copy number gain results in a milder phenotype. The clinical features suggesting a neurocristopathy may be explained by animal model studies indicating involvement of the Mediator complex subunit 13 in neural crest induction.

show abstract

A recurrent mutation in MED12 leading to R961W causes Opitz-Kaveggia syndrome

Cited by 175 publications

References 15 publications

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

Chronic lymphocytic leukemia: Time to go past genomics?

Dosage changes of MED13L further delineate its role in congenital heart defects and intellectual disability

Contact Info

Product

Resources

About