title: Identification and functional analysis of a novel LHX1 mutation associated with congenital absence of the uterus and vagina.
abstract: Congenital absence of the uterus and vagina (CAUV) is the most extreme female Müllerian duct abnormality. Several researches proposed that genetic factors contributed to this disorder, whereas the precise genetic mechanism is far from full elucidation. Here, utilizing whole-exome sequencing (WES), we identified one novel missense mutation in LHX1 (NM_005568: c.G1108A, p.A370T) in one of ten unrelated patients diagnosed with CAUV. This mutation was absent from public databases and our internal database. Through the luciferase reporter analysis, we found that the mutation could change the transcriptional activity of LHX1 and its effect on the regulation of the downstream target gene GSC, which might be associated with urogenital system development. In short, we concluded that the LHX1 may be a pathogenic gene of CAUV. Our results demonstrate the power of whole exome sequencing and gene prioritization approach as diagnostic tools in clinical practice that help make genetic diagnosis of CAUV.
authors.affiliation: Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.|Graduate School, Peking Union Medical College, Beijing, China.|Center for Genetics, National Research Institute for Family Planning, Beijing, China.
authors.forename: Wei
authors.initials: W
authors.lastname: Zhang
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.|Department of Psychiatry and Centre for Genomic Sciences, Li KaShing Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
authors.forename: Xueya
authors.initials: X
authors.lastname: Zhou
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Liyang
authors.initials: L
authors.lastname: Liu
authors.affiliation: Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhu
authors.affiliation: Department of Obstetrics and Gynecology, Peking Union Medical College Hospital, Beijing, China.
authors.forename: Chunmei
authors.initials: C
authors.lastname: Liu
authors.affiliation: Center for Genetics, National Research Institute for Family Planning, Beijing, China.
authors.forename: Hong
authors.initials: H
authors.lastname: Pan
authors.affiliation: Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Xing
authors.affiliation: Department of Medical Genetics, School of Basic Medical Sciences, Capital Medical University, Beijing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Wang
authors.affiliation: Center for Genetics, National Research Institute for Family Planning, Beijing, China.
authors.forename: Xi
authors.initials: X
authors.lastname: Wang
authors.affiliation: MOE Key Laboratory of Bioinformatics, Bioinformatics Division and Center for Synthetic and Systems Biology, TNLIST/Department of Automation, Tsinghua University, Beijing, China.
authors.forename: Xuegong
authors.initials: X
authors.lastname: Zhang
authors.affiliation: Reproductive Medicine Center, The First Affiliated Hospital of Anhui Medical University, Hefei, China.
authors.forename: Yunxia
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Graduate School, Peking Union Medical College, Beijing, China.|Center for Genetics, National Research Institute for Family Planning, Beijing, China.
authors.forename: Binbin
authors.initials: B
authors.lastname: Wang
mesh_terms: D058489:46, XX Disorders of Sex Development / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D000013:Congenital Abnormalities / Q000175:diagnosis / Q000235:genetics* / Q000378:metabolism; D004252:DNA Mutational Analysis; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease; D051956:Goosecoid Protein / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D060850:LIM-Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D009095:Mullerian Ducts / Q000002:abnormalities* / Q000378:metabolism; D020125:Mutation, Missense; D010641:Phenotype; D011401:Promoter Regions, Genetic; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014158:Transcription, Genetic; D014162:Transfection; D000073359:Exome Sequencing
chemical_list: C497992:GSC protein, human; D005819:Genetic Markers; D051956:Goosecoid Protein; C085473:LHX1 protein, human; D060850:LIM-Homeodomain Proteins; D014157:Transcription Factors
keywords: LHX1; Müllerian duct abnormality; congenital absence of the uterus and vagina; transcriptional activity; whole exome sequencing