title: Mayer-Rokitansky-Küster-Hauser syndrome discordance in monozygotic twins: matrix metalloproteinase 14, low-density lipoprotein receptor-related protein 10, extracellular matrix, and neoangiogenesis genes identified as candidate genes in a tissue-specific mosaicism.
abstract: OBJECTIVE
  To find a potential underlying cause for Mayer-Rokitansky-Küster-Hauser syndrome (MRKHS) discordance in monozygotic twins.
  
  
  METHODS
  Prospective comparative study.
  
  
  METHODS
  University hospital.
  
  
  METHODS
  Our study genetically analyzed 5 MRKHS-discordant monozygotic twin pairs with the unique opportunity to include saliva and rudimentary uterine tissue.
  
  
  METHODS
  Blood, saliva, or rudimentary uterine tissue from five MRKHS-discordant twins was analyzed and compared between twin pairs as well as within the same individual where applicable. We used copy number variations (CNVs) to identify differences.
  
  
  METHODS
  CNVs in blood, rudimentary uterine tissue, and saliva, network analysis, and review of the literature.
  
  
  RESULTS
  One duplication found in the affected twin included two genes, matrix metalloproteinase 14 (MMP14) and low-density lipoprotein receptor-related protein 10 (LRP10), which have known functions in the embryonic development of the uterus and endometrium. The duplicated region was detected in rudimentary uterine tissue from the same individual but not in saliva, making a tissue-specific mosaicism a possible explanation for twin discordance. Additional network analysis revealed important connections to differentially expressed genes from previous studies. These genes encode several molecules involved in extracellular matrix (ECM) remodeling and neoangiogenesis.
  
  
  CONCLUSIONS
  MMP-14, LRP-10, ECM, and neoangiogenesis genes are identified as candidate genes in a tissue-specific mosaicism. The detected clusters provide evidence of deficient vascularization during uterine development and/or disturbed reorganization of ECM components, potentially during müllerian duct elongation signaled by the embryologically relevant phosphatidylinositol 3-kinase/protein kinase B pathway. Therefore, we consider these genes to be new candidates in the manifestation of MRKHS.
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany. Electronic address: katharina.rall@med.uni-tuebingen.de.
authors.forename: Katharina
authors.initials: K
authors.lastname: Rall
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Eisenbeis
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany.
authors.forename: Gianmaria
authors.initials: G
authors.lastname: Barresi
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Rückner
authors.affiliation: Department of Medical Genetics, Microarray Facility, Tübingen University Hospital, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Walter
authors.affiliation: Department of Medical Genetics, Microarray Facility, Tübingen University Hospital, Tübingen, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Poths
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany.
authors.forename: Diethelm
authors.initials: D
authors.lastname: Wallwiener
authors.affiliation: Department of Medical Genetics, Microarray Facility, Tübingen University Hospital, Tübingen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Riess
authors.affiliation: Department of Medical Genetics, Microarray Facility, Tübingen University Hospital, Tübingen, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Bonin
authors.affiliation: Department of Obstetrics and Gynecology and Center for Rare Female Genital Malformations, Tübingen, Germany.
authors.forename: Sara
authors.initials: S
authors.lastname: Brucker
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000175:diagnosis / Q000235:genetics*; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics*; D005109:Extracellular Matrix / Q000235:genetics*; D005260:Female; D053263:Gene Regulatory Networks / Q000235:genetics; D056726:Genetic Association Studies / Q000379:methods*; D006801:Humans; D026502:LDL-Receptor Related Proteins / Q000235:genetics*; D053511:Matrix Metalloproteinase 14 / Q000235:genetics*; D009030:Mosaicism; D009095:Mullerian Ducts / Q000002:abnormalities*; D009389:Neovascularization, Pathologic / Q000175:diagnosis / Q000235:genetics; D011446:Prospective Studies; D014430:Twins, Monozygotic / Q000235:genetics*
chemical_list: D026502:LDL-Receptor Related Proteins; C510813:LRP10 protein, human; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14
keywords: CNV; MRKH syndrome; Uterovaginal aplasia; monozygotic discordant twins; mosaicism