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Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene.

Publication ,  Journal Article
Demura, M; Martin, RM; Shozu, M; Sebastian, S; Takayama, K; Hsu, W-T; Schultz, RA; Neely, K; Bryant, M; Mendonca, BB; Hanaki, K; Kanzaki, S ...
Published in: Human molecular genetics
November 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.

Published In

Human molecular genetics

DOI

EISSN

1460-2083

ISSN

0964-6906

Publication Date

November 2007

Volume

16

Issue

21

Start / End Page

2529 / 2541

Related Subject Headings

  • Transcription, Genetic
  • Syndrome
  • Recombination, Genetic
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Pedigree
  • Mutation
  • Male
  • Humans
  • Heterozygote
 

Citation

APA
Chicago
ICMJE
MLA
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Demura, M., Martin, R. M., Shozu, M., Sebastian, S., Takayama, K., Hsu, W.-T., … Bulun, S. E. (2007). Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Human Molecular Genetics, 16(21), 2529–2541. https://doi.org/10.1093/hmg/ddm145
Demura, Masashi, Regina M. Martin, Makio Shozu, Siby Sebastian, Kazuto Takayama, Wei-Tong Hsu, Roger A. Schultz, et al. “Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene.Human Molecular Genetics 16, no. 21 (November 2007): 2529–41. https://doi.org/10.1093/hmg/ddm145.
Demura M, Martin RM, Shozu M, Sebastian S, Takayama K, Hsu W-T, et al. Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Human molecular genetics. 2007 Nov;16(21):2529–41.
Demura, Masashi, et al. “Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene.Human Molecular Genetics, vol. 16, no. 21, Nov. 2007, pp. 2529–41. Epmc, doi:10.1093/hmg/ddm145.
Demura M, Martin RM, Shozu M, Sebastian S, Takayama K, Hsu W-T, Schultz RA, Neely K, Bryant M, Mendonca BB, Hanaki K, Kanzaki S, Rhoads DB, Misra M, Bulun SE. Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene. Human molecular genetics. 2007 Nov;16(21):2529–2541.
Journal cover image

Published In

Human molecular genetics

DOI

EISSN

1460-2083

ISSN

0964-6906

Publication Date

November 2007

Volume

16

Issue

21

Start / End Page

2529 / 2541

Related Subject Headings

  • Transcription, Genetic
  • Syndrome
  • Recombination, Genetic
  • RNA, Messenger
  • Promoter Regions, Genetic
  • Pedigree
  • Mutation
  • Male
  • Humans
  • Heterozygote