FOXL2 inactivation by a translocation 171 kb away: analysis of 500 kb of chromosome 3 for candidate long-range regulatory sequences

• Published in: Genomics (San Diego, Calif.) Vol. 83; no. 5; pp. 757 - 764
• Main Authors: Crisponi, Laura, Uda, Manuela, Deiana, Manila, Loi, Angela, Nagaraja, Ramaiah, Chiappe, Francesca, Schlessinger, David, Cao, Antonio, Pilia, Giuseppe
• Format: Journal Article
• Language: English
• Published: San Diego, CA Elsevier Inc 01-05-2004; Elsevier
• Subjects: Animals; Base Sequence; Biological and medical sciences; Chromosome Breakage - genetics; Chromosomes, Human, Pair 3 - genetics; Coatomer Protein - genetics; Conserved Sequence - genetics; CpG Islands - genetics; DNA-Binding Proteins - genetics; Enhancer; Exons - genetics; Forkhead Box Protein L2; Forkhead protein; Forkhead Transcription Factors; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation - genetics; Genes. Genome; Genetics of eukaryotes. Biological and molecular evolution; Genomic; Genomics; Goats - genetics; Humans; Introns - genetics; Male; Mice; Mitochondrial Proteins - genetics; Molecular and cellular biology; Molecular genetics; Molecular Sequence Data; Promoter; Regulation of gene expression; Regulatory Sequences, Nucleic Acid - genetics; Ribosomal Proteins - genetics; RNA, Messenger - genetics; RNA, Messenger - metabolism; Testis - metabolism; Transcription; Transcription Factors - genetics; Translocation; Translocation, Genetic - genetics; Translocation; Promoter; Transcription; Enhancer; Forkhead protein; Regulation of gene expression; Genomic; Analysis; Genomics; Regulatory sequence; Chromosome 3; Inactivation
• ISSN: 0888-7543; 1089-8646
• DOI: 10.1016/j.ygeno.2003.11.010

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.