Mapping of a responsible region for sex reversal upstream of Sox9 by production of mice with serial deletion in a genomic locus.
Mapping of a responsible region for sex reversal upstream of Sox9 by production of mice with serial deletion in a genomic locus.
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通过在基因组基因座中产生串行缺失的小鼠，将SOX9上游的性逆转的负责任区域映射。
DOI：
10.1038/s41598-018-35746-0
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发表时间：
2018-11-30
影响因子：
4.6
通讯作者：
Takada S
中科院分区：
文献类型：
--
作者：
Ogawa Y;Terao M;Hara S;Tamano M;Okayasu H;Kato T;Takada S
Sox 9在睾丸形成中起关键作用。通过对4个家族性性发育障碍病例进行定位，发现位于SOX 9上游的32.5 kb序列是一个常见的缺失区，并命名为XY性逆转区（XYSR）。为了缩小XYSR中的负责序列，我们通过应用CRISPR/Cas9系统产生了XYSR中具有一系列缺失的突变小鼠，使用靶向该区域中几个核糖核酸酶（kb）间隔的sgRNA的混合物。当小鼠中的整个XYSR对应序列在XY核型个体中缺失时，突变导致雌性后代，表明SOX 9/Sox 9通过XYSR的表达机制在人和小鼠中是保守的。在4.8 kb缺失的小鼠中发现雄性到雌性的性逆转。我们确定了一个在人类、小鼠和负鼠中保守的序列，在小鼠中缺失该序列（783 bp）导致雄性到雌性的性别逆转。该序列包括最近报道的Sox 9的关键性腺增强子。虽然不能得出结论，人类序列是负责XYSR，这是可能的。该方法适用于致病性缺失的责任序列的精细定位，特别是关于罕见疾病。
Sox9 plays critical roles in testis formation. By mapping four familial cases of disorders of sexual development, a 32.5 kb sequence located far upstream of SOX9 was previously identified as being a commonly deleted region and named the XY sex reversal region (XYSR). To narrow down a responsible sequence in XYSR, we generated mutant mice with a series of deletions in XYSR by application of the CRISPR/Cas9 system, using a mixture of sgRNAs targeting several kilobase (kb) intervals in the region. When the whole XYSR corresponding sequence in mice was deleted in XY karyotype individuals, the mutation resulted in female offspring, suggesting that an expression mechanism of SOX9/Sox9 through XYSR is conserved in human and mouse. Male-to-female sex reversal was found in mice with a 4.8 kb deletion. We identified a sequence conserved among humans, mice, and opossum, the deletion of which (783 bp) in mice resulted in male-to-female sex reversal. The sequence includes a recently reported critical gonad enhancer for Sox9. Although it cannot be concluded that the human sequence is responsible for XYSR, it is likely. This method is applicable for fine mapping of responsible sequences for disease-causing deletions especially with regard to rare diseases.
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影响因子：
4.6
作者：
Inui M;Miyado M;Igarashi M;Tamano M;Kubo A;Yamashita S;Asahara H;Fukami M;Takada S
通讯作者：
Takada S
影响因子：
2
作者：
Katoh-Fukui Y;Igarashi M;Nagasaki K;Horikawa R;Nagai T;Tsuchiya T;Suzuki E;Miyado M;Hata K;Nakabayashi K;Hayashi K;Matsubara Y;Baba T;Morohashi K;Igarashi A;Ogata T;Takada S;Fukami M
通讯作者：
Fukami M
影响因子：
3.5
作者：
Leipoldt, M.;Erdel, M.;Scherer, G.
通讯作者：
Scherer, G.
影响因子：
7
作者：
Schwartz, S;Zhang, Z;Miller, W
通讯作者：
Miller, W
DOI：
10.1126/science.1232033
发表时间：
2013-02-15
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Mali P;Yang L;Esvelt KM;Aach J;Guell M;DiCarlo JE;Norville JE;Church GM
通讯作者：
Church GM