Human Molecular Genetics Advance Access originally published online on June 21, 2007
Human Molecular Genetics 2007 16(21):2529-2541; doi:10.1093/hmg/ddm145
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Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene
1 Division of Reproductive Biology Research, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA, 2 Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Divisao de Endocrinologia, Hospital das Clinicas, Faculdade de Medicina, Universidade de Sao Paulo, Sao Paulo 01065-970, Brazil, 3 Department of Obstetrics and Gynecology, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan, 4 Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA, 5 Department of Obstetrics and Gynecology, Tohoku University School of Medicine, Sendai 980-8574, Japan, 6 Department of Pediatrics, Rush Medical School, Chicago, IL 60612, USA, 7 Department of Pathology, University of Texas Southwestern Medical Center at Dallas, Dallas, TX 75390, USA, 8 Department of Pediatrics, Stanford University, Palo Alto, CA 94305, USA, 9 Department of Pediatrics, Children's Hospital, Los Angeles, CA 90027, USA, 10 Division of Pediatrics and Perinatology, Tottori University, Yonago, Japan and 11 Pediatric Endocrine Unit, Mass General Hospital for Children and Harvard Medical School, Boston, MA 02114, USA
* To whom correspondence should be addressed at: Division of Reproductive Biology Research, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Suite 4-123, Chicago, IL 60611 USA. Tel: +1 3125030520; Fax: +1 3125030095; Email: s-bulun{at}northwestern.edu
Received March 29, 2007; Revised June 1, 2007; Accepted June 5, 2007
Production of appropriate quantities of estrogen in various tissues is essential for human physiology. A single gene (CYP19), regulated via tissue-specific promoters, encodes the enzyme aromatase, which catalyzes the key step in estrogen biosynthesis. Aromatase excess syndrome is inherited as autosomal dominant and characterized by high systemic estrogen levels, short stature, prepubertal gynecomastia and testicular failure in males, and premature breast development and uterine pathology in females. The underlying genetic mechanism is poorly understood. Here, we characterize five distinct heterozygous rearrangements responsible for aromatase excess syndrome in three unrelated families and two individuals (nine patients). The constitutively active promoter of one of five ubiquitously expressed genes located within the 11.2 Mb region telomeric to the CYP19 gene in chromosome 15q21 cryptically upregulated aromatase expression in several tissues. Four distinct inversions reversed the transcriptional direction of the promoter of a gene (CGNL1, TMOD3, MAPK6 or TLN2), placing it upstream of the CYP19 coding region in the opposite strand, whereas a deletion moved the promoter of a fifth gene (DMXL2), normally transcribed from the same strand, closer to CYP19. The proximal breakpoints of inversions were located 17–185 kb upstream of the CYP19 coding region. Sequences at the breakpoints suggested that the inversions were caused by intrachromosomal nonhomologous recombination. Splicing the untranslated exon downstream of each promoter onto the identical junction upstream of the translation initiation site created CYP19 mRNA encoding functional aromatase protein. Taken together, small rearrangements may create cryptic promoters that direct inappropriate transcription of CYP19 or other critical genes.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.