MAMLD1 and 46,XY Disorders of Sex Development
MAMLD1 and 46,XY Disorders of Sex Development
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DOI：
10.1055/s-0032-1324725
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发表时间：
2012-09-01
影响因子：
2.7
通讯作者：
Fukami, Maki
中科院分区：
文献类型：
--
作者：
Ogata, Tsutomu;Sano, Shinichirou;Fukami, Maki
MAMLD1是新近发现的一种46，XY性发育障碍(DSD)的致病基因，其临床表型为尿道下裂。到目前为止，已经在6名患者中发现了涉及MAMLD1的微缺失，并在6名患者中发现了确定的突变(无义和移码突变，预计会经历无义介导的mRNA衰退[NMD])。此外，特异的MAMLD1cSNP(S)和单倍型可能是尿道下裂的易感因素。此外，体外研究表明：(1)小鼠同源基因在胎儿Sertoli和Leyig细胞中表达，大约在性发育的关键时期；(2)瞬时的MamId1敲除导致睾酮的产生显著减少，主要是因为17α-羟化和Cypl7a1在小鼠间质肿瘤细胞中的表达受损；(3)MAMLD1定位于核体并反式激活非规范的Notch靶基因Hair/Enhancer of Split 3的启动子活性，而没有明显的DNA结合能力；以及(4)MAMLD1受类固醇生成因子1(SF1)的调节。这些发现表明，MAMLD1突变导致46，XY DSD的主要原因是在性发育的关键时期睾丸激素的分泌受到影响。进一步的研究将为参与胎儿睾酮产生的分子网络提供有用的信息。
MAMLD1 (mastermind-like domain containing 1) is a recently discovered causative gene for 46,XY disorders of sex development (DSD), with hypospadias as the salient clinical phenotype. To date, microdeletions involving MAMLD1 have been identified in six patients, and definitive mutations (nonsense and frameshift mutations that are predicted to undergo nonsense mediated mRNA decay [NMD]) have been found in six patients. In addition, specific MAMLD1 cSNP(s) and haplotype may constitute a susceptibility factor for hypospadias. Furthermore, in vitro studies have revealed that (1) the mouse homolog is expressed in fetal Sertoli and Leydig cells around the critical period for sex development; (2) transient MamId1 knockdown results in significantly reduced testosterone production primarily because of compromised 17 alpha-hydroxylation and Cypl7a1 expression in Murine Leydig tumor cells; (3) MAMLD1 localizes to the nuclear bodies and transactivates the promoter activity of a non-canonical Notch target gene hairy/enhancer of split 3, without demonstrable DNA-binding capacity; and (4) MAMLD1 is regulated by steroidogenic factor 1 (SF1). These findings suggest that the MAMLD1 mutations cause 46,XY DSD primarily because of compromised testosterone production around the critical period for sex development. Further studies will provide useful information for the molecular network involved in fetal testosterone production.