Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development.
Nonsense-associated altered splicing of MAP3K1 in two siblings with 46,XY disorders of sex development.
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DOI：
10.1038/s41598-020-74405-1
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发表时间：
2020-10-15
影响因子：
4.6
通讯作者：
Fukami M
中科院分区：
文献类型：
--
作者：
Igarashi M;Masunaga Y;Hasegawa Y;Kinjo K;Miyado M;Saitsu H;Kato-Fukui Y;Horikawa R;Okubo Y;Ogata T;Fukami M
虽然由于单核苷酸变异导致的剪接错误代表了单基因疾病的常见原因，但只有少数变异显示在外显子中产生新的剪接位点。在这里，我们报告了一个MAP 3 K1剪接变异体在两个兄弟姐妹与46，XY性发育障碍。患者携带母体来源的c.2254C>T变异。该变体最初被认为是无义取代，导致无义介导的mRNA衰变（p.Gln752Ter）;然而，淋巴母细胞系的RT-PCR显示，该变体创建了一个新的剪接供体位点，并导致39个氨基酸缺失（p.Gln752_Arg790del）。所有来自变异等位基因的转录物似乎都经历了改变的剪接。这两名患者表现出男性化不足的生殖器，有和没有高促性腺激素。庚酸替尼酯注射和双氢睾酮软膏应用仅使其阴茎长度略有增加。与对照组相比，患者生殖器皮肤成纤维细胞中二氢睾酮诱导的APOD反式激活不太显著。这项研究提供了一个无义相关的剪接改变的例子，其中创建了一个高效的外显子剪接位点。此外，我们的数据，结合以前的数据表明MAP 3 K1和雄激素受体信号之间的关联，意味着睾丸发育不全和雄激素不敏感的组合可能是一个独特的表型MAP 3 K1异常。
Although splicing errors due to single nucleotide variants represent a common cause of monogenic disorders, only a few variants have been shown to create new splice sites in exons. Here, we report an MAP3K1 splice variant identified in two siblings with 46,XY disorder of sex development. The patients carried a maternally derived c.2254C>T variant. The variant was initially recognized as a nonsense substitution leading to nonsense-mediated mRNA decay (p.Gln752Ter); however, RT-PCR for lymphoblastoid cell lines showed that this variant created a new splice donor site and caused 39 amino acid deletion (p.Gln752_Arg790del). All transcripts from the variant allele appeared to undergo altered splicing. The two patients exhibited undermasculinized genitalia with and without hypergonadotropism. Testosterone enanthate injections and dihydrotestosterone ointment applications yielded only slight increase in their penile length. Dihydrotestosterone-induced APOD transactivation was less significant in patients’ genital skin fibroblasts compared with that in control samples. This study provides an example of nonsense-associated altered splicing, in which a highly potent exonic splice site was created. Furthermore, our data, in conjunction with the previous data indicating the association between MAP3K1 and androgen receptor signaling, imply that the combination of testicular dysgenesis and androgen insensitivity may be a unique phenotype of MAP3K1 abnormalities.
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影响因子：
14.9
作者：
Desmet FO;Hamroun D;Lalande M;Collod-Béroud G;Claustres M;Béroud C
通讯作者：
Béroud C
影响因子：
3.5
作者：
Loke, J.;Ostrer, H.
通讯作者：
Ostrer, H.
DOI：
10.1038/nrm3454
发表时间：
2012-11
期刊：
Nature reviews. Molecular cell biology
影响因子：
--
作者：
通讯作者：
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影响因子：
4.4
作者：
Littink, Karin W.;Pott, Jan-Willem R.;den Hollander, Anneke I.
通讯作者：
den Hollander, Anneke I.
影响因子：
3.9
作者：
Musante, Luciana;Kunde, Stella-Amrei;Kalscheuer, Vera M.
通讯作者：
Kalscheuer, Vera M.