The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene

Schwartz, Charles E.; Tarpey, Patrick; Lubs, Herbert A.; Verloes, Alain; May, Melanie; Risheg, Hiba; Friez, Michael J.; Futreal, P. Andrew; Edkins, Sarah; Teague, Jon W.; Briault, Sylvain; Skinner, Cindy; Bauer-Carlin, Astrid; Simensen, Richard J.; Joseph, Sumy; Jones, Julie R.; Gécz, Jozef; Stratton, Michael R.; Raymond, F. Lucy; Stevenson, Roger E.

doi:10.1136/jmg.2006.048637

Cited by 159 publications

(147 citation statements)

References 25 publications

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“…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

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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.

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Section: Discussionmentioning

confidence: 99%

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

et al. 2013

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“…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. For the other members of the Mediator complex, the following disease associations have been reported so far: an 800 kb heterozygous deletion including MED13 in a patient with ID, cataract and hearing loss, 6 association of infantile cerebral and cerebellar atrophy with a homozygous missense mutation in MED17, 7 co-segregation of a missense mutation in MED23 with nonsyndromic autosomal recessive ID 8 and a homozygous missense mutation of MED25 in a family with Charcot-Marie-Tooth neuropathy.…”

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

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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.

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“…In this regard, our interest has centered on two related XLID disorders, FG (or Opitz-Kaveggia) syndrome and Lujan (or Lujan-Fryns) syndrome. In addition to ID, FG and Lujan syndromes share several overlapping clinical manifestations, including agenesis/dysgenesis of the corpus callosum, macrocephaly, hypotonia, craniofacial dysmorphisms, seizures, and behavioral disturbances (3,4). Although neither condition was originally considered in the differential diagnosis of the other, these two syndromes were recently found to be allelic, arising from different missense mutations in the Xq13 gene encoding MED12, a subunit of the RNA polymerase II transcriptional Mediator (3)(4)(5).…”

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confidence: 99%

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

Zhou

Spaeth

Kim

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Recurrent missense mutations in the RNA polymerase II Mediator subunit MED12 are associated with X-linked intellectual disability (XLID) and multiple congenital anomalies, including craniofacial, musculoskeletal, and behavioral defects in humans with FG (or Opitz-Kaveggia) and Lujan syndromes. However, the molecular mechanism(s) underlying these phenotypes is poorly understood. Here we report that MED12 mutations R961W and N1007S causing FG and Lujan syndromes, respectively, disrupt a Mediator-imposed constraint on GLI3-dependent Sonic Hedgehog (SHH) signaling. We show that the FG/R961W and Lujan/N1007S mutations disrupt the gene-specific association of MED12 with a second Mediator subunit, CDK8, identified herein to be a suppressor of GLI3 transactivation activity. In FG/R961W and Lujan/N1007S patient-derived cells, we document enhanced SHH pathway activation and GLI3-target gene induction coincident with impaired recruitment of CDK8 onto promoters of GLI3-target genes, but not non-GLI3-target genes. Together, these findings suggest that dysregulated GLI3-dependent SHH signaling contributes to phenotypes of individuals with FG and Lujan syndromes and further reveal a basis for the gene-specific manifestation of pathogenic mutations in a global transcriptional coregulator.

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The original Lujan syndrome family has a novel missense mutation (p.N1007S) in the MED12 gene

Cited by 159 publications

References 25 publications

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

MED12 mutations in leiomyosarcoma and extrauterine leiomyoma

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

MED12 mutations link intellectual disability syndromes with dysregulated GLI3-dependent Sonic Hedgehog signaling

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