title: FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences.
abstract: A translocation breakpoint 171 kb 5' of the transcription start of FOXL2 causes blepharophimosis/ptosis/epicanthus inversus syndrome (BPES) and associated premature ovarian failure. The breakpoint falls within another gene, MRPS22, that has been sequenced in 500 kb of continuous DNA. MRPS22 encodes 20 exons and a number of alternative transcripts. Three CpG islands (>91% identical) are followed by noncoding exons 4-12 and coding exons 13-20. The 3'UTR extends into the 3'UTR of COPB2. Based on the sequence, three reported translocations that cause BPES all fall within intron 6 of MRPS22. Comparisons reveal conserved segments in introns 6, 11, and 12 of human and mouse. Notably intron 11 sequence is also deleted in goat PIS syndrome (which combines craniofacial defects, female infertility, and XX sex reversal). The conserved sequences are candidates for models in which they are distant enhancers or otherwise affect higher order chromatin structure to impose long-range cis regulation of FOXL2 expression.
authors.affiliation: Istituto di Neurogenetica e Neurofarmacologia, Consiglio Nazionale delle Ricerche, CNR, Via Jenner, Cagliari 09121, Italy.
authors.forename: Laura
authors.initials: L
authors.lastname: Crisponi
authors.forename: Manuela
authors.initials: M
authors.lastname: Uda
authors.forename: Manila
authors.initials: M
authors.lastname: Deiana
authors.forename: Angela
authors.initials: A
authors.lastname: Loi
authors.forename: Ramaiah
authors.initials: R
authors.lastname: Nagaraja
authors.forename: Francesca
authors.initials: F
authors.lastname: Chiappe
authors.forename: David
authors.initials: D
authors.lastname: Schlessinger
authors.forename: Antonio
authors.initials: A
authors.lastname: Cao
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Pilia
mesh_terms: D000818:Animals; D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics*; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics*; D020756:Coatomer Protein / Q000235:genetics; D017124:Conserved Sequence / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons / Q000235:genetics; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; D005786:Gene Expression Regulation / Q000235:genetics*; D023281:Genomics; D006041:Goats / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics; D008297:Male; D051379:Mice; D024101:Mitochondrial Proteins / Q000235:genetics; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D012269:Ribosomal Proteins / Q000235:genetics; D013737:Testis / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics*; D014178:Translocation, Genetic / Q000235:genetics*
chemical_list: D020756:Coatomer Protein; D004268:DNA-Binding Proteins; C421604:FOXL2 protein, human; D000074842:Forkhead Box Protein L2; D051858:Forkhead Transcription Factors; C498893:Foxl2 protein, mouse; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; D012269:Ribosomal Proteins; D014157:Transcription Factors; C066492:ribosomal protein S22