A missense variant at the RAC1-PAK1 binding site of RAC1 inactivates downstream signaling in VACTERL association

被引:4
作者
Seyama, Rie [1 ,2 ]
Nishikawa, Masashi [3 ,4 ]
Uchiyama, Yuri [1 ,5 ]
Hamada, Keisuke [6 ]
Yamamoto, Yuka [2 ]
Takeda, Masahiro [7 ]
Ochi, Takanori [7 ]
Kishi, Monami [8 ]
Suzuki, Toshifumi [2 ,9 ]
Hamanaka, Kohei [1 ]
Fujita, Atsushi [1 ]
Tsuchida, Naomi [1 ,5 ]
Koshimizu, Eriko [1 ]
Misawa, Kazuharu [1 ,10 ]
Miyatake, Satoko [1 ,11 ]
Mizuguchi, Takeshi [1 ]
Makino, Shintaro [12 ]
Yao, Takashi [13 ]
Ito, Hidenori [3 ]
Itakura, Atsuo [2 ]
Ogata, Kazuhiro [6 ]
Nagata, Koh-ichi [3 ,14 ]
Matsumoto, Naomichi [1 ]
机构
[1] Yokohama City Univ, Grad Sch Med, Dept Human Genet, Fukuura 3-9,Kanazawa Ku, Yokohama, Kanagawa 2360004, Japan
[2] Juntendo Univ, Fac Med, Dept Obstet & Gynecol, Tokyo, Japan
[3] Aichi Dev Disabil Ctr, Inst Dev Res, Dept Mol Neurobiol, 713-8 Kamiya, Kasugai, Aichi 4800392, Japan
[4] Nagoya Univ, Dept Biol Sci, Nagoya, Aichi, Japan
[5] Yokohama City Univ Med, Dept Rare Dis Genom, Yokohama, Kanagawa, Japan
[6] Yokohama City Univ, Grad Sch Med, Dept Biochem, Yokohama, Kanagawa, Japan
[7] Juntendo Univ, Sch Med, Dept Pediat Surg, Tokyo, Japan
[8] Juntendo Univ, Sch Med, Dept Human Pathol, Tokyo, Japan
[9] Keiai Hosp, Dept Obstet & Gynecol, Saitama, Japan
[10] RIKEN Ctr Adv Intelligence Project, Tokyo, Japan
[11] Yokohama City Univ Med, Dept Clin Genet, Yokohama, Kanagawa, Japan
[12] Juntendo Univ, Urayasu Hosp, Dept Obstet & Gynecol, Urayasu, Japan
[13] Juntendo Univ, Grad Sch Med, Dept Human Pathol, Tokyo, Japan
[14] Nagoya Univ, Grad Sch Med, Dept Neurochem, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan
来源
SCIENTIFIC REPORTS | 2023年 / 13卷 / 01期
基金
日本学术振兴会;
关键词
RHO GTPASES; KINASE; MUTATIONS; HEDGEHOG; JNK;
D O I
10.1038/s41598-023-36381-0
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
RAC1 at 7p22.1 encodes a RAC family small GTPase that regulates actin cytoskeleton organization and intracellular signaling pathways. Pathogenic RAC1 variants result in developmental delay and multiple anomalies. Here, exome sequencing identified a rare de novo RAC1 variant [NM_018890.4:c.118T>C p.(Tyr40His)] in a male patient. Fetal ultrasonography indicated the patient to have multiple anomalies, including persistent left superior vena cava, total anomalous pulmonary venous return, esophageal atresia, scoliosis, and right-hand polydactyly. After birth, craniofacial dysmorphism and esophagobronchial fistula were confirmed and VACTERL association was suspected. One day after birth, the patient died of respiratory failure caused by tracheal aplasia type III. The molecular mechanisms of pathogenic RAC1 variants remain largely unclear; therefore, we biochemically examined the pathophysiological significance of RAC1-p.Tyr40His by focusing on the best characterized downstream effector of RAC1, PAK1, which activates Hedgehog signaling. RAC1-p.Tyr40His interacted minimally with PAK1, and did not enable PAK1 activation. Variants in the RAC1 Switch II region consistently activate downstream signals, whereas the p.Tyr40His variant at the RAC1-PAK1 binding site and adjacent to the Switch I region may deactivate the signals. It is important to accumulate data from individuals with different RAC1 variants to gain a full understanding of their varied clinical presentations.
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页数:11
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