Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene
Regional rearrangements in chromosome 15q21 cause formation of cryptic promoters for the CYP19 (aromatase) gene
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DOI：
10.1093/hmg/ddm145
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发表时间：
2007-11-01
影响因子：
3.5
通讯作者：
Bulun, Serdar E.
中科院分区：
文献类型：
--
作者：
Demura, Masashi;Martin, Regina M.;Bulun, Serdar E.
在各种组织中产生适量的雌激素是人体生理所必需的。由组织特异性启动子调控的单基因(CYP19)编码芳香酶，该酶催化雌激素生物合成的关键步骤。芳香酶过度综合征是一种常染色体显性遗传，其特征是全身雌激素水平高，男性身材矮小，青春期前女性乳房发育和睾丸功能衰竭，女性乳房发育和子宫病理早熟。人们对潜在的遗传机制知之甚少。在这里，我们在三个无关的家系和两个个体(九名患者)中描述了导致芳香酶过量综合征的五个不同的杂合子重排。位于染色体15q21上CYP19基因端粒11.2Mb区域的5个普遍表达基因中的一个的结构性活性启动子在几个组织中隐匿上调芳香酶的表达。四个不同的反转逆转了一个基因(CGNL1、TMOD3、MAPK6或TLN2)启动子的转录方向，将其置于CYP19编码区上游的相反链中，而缺失则使第五个基因(DMXL2)的启动子更接近CYP19，该基因通常从同一链转录。倒位的近端断裂点位于CYP19编码区上游17-185kb。断裂点上的序列表明，这些倒位是由染色体内的非同源重组引起的。将每个启动子下游的未翻译外显子拼接到翻译起始点上游的相同连接上，产生了编码功能性芳香酶蛋白的CYP19mRNA。总而言之，微小的重排可能会产生隐蔽的启动子，指导不适当的CYP19或其他关键基因的转录。
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.