A novel NONO variant that causes developmental delay and cardiac phenotypes
Abstract The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g.,...
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-01-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-27770-6 |
| _version_ | 1797864692003110912 |
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| author | Toshiyuki Itai Atsushi Sugie Yohei Nitta Ryuto Maki Takashi Suzuki Yoichi Shinkai Yoshihiro Watanabe Yusuke Nakano Kazushi Ichikawa Nobuhiko Okamoto Yasuhiro Utsuno Eriko Koshimizu Atsushi Fujita Kohei Hamanaka Yuri Uchiyama Naomi Tsuchida Noriko Miyake Kazuharu Misawa Takeshi Mizuguchi Satoko Miyatake Naomichi Matsumoto |
| author_facet | Toshiyuki Itai Atsushi Sugie Yohei Nitta Ryuto Maki Takashi Suzuki Yoichi Shinkai Yoshihiro Watanabe Yusuke Nakano Kazushi Ichikawa Nobuhiko Okamoto Yasuhiro Utsuno Eriko Koshimizu Atsushi Fujita Kohei Hamanaka Yuri Uchiyama Naomi Tsuchida Noriko Miyake Kazuharu Misawa Takeshi Mizuguchi Satoko Miyatake Naomichi Matsumoto |
| author_sort | Toshiyuki Itai |
| collection | DOAJ |
| description | Abstract The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms. |
| first_indexed | 2024-04-09T22:56:06Z |
| format | Article |
| id | doaj.art-5f0d682f4c2d4892ad0ade18f7ec2c5c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T22:56:06Z |
| publishDate | 2023-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-5f0d682f4c2d4892ad0ade18f7ec2c5c2023-03-22T11:14:36ZengNature PortfolioScientific Reports2045-23222023-01-011311910.1038/s41598-023-27770-6A novel NONO variant that causes developmental delay and cardiac phenotypesToshiyuki Itai0Atsushi Sugie1Yohei Nitta2Ryuto Maki3Takashi Suzuki4Yoichi Shinkai5Yoshihiro Watanabe6Yusuke Nakano7Kazushi Ichikawa8Nobuhiko Okamoto9Yasuhiro Utsuno10Eriko Koshimizu11Atsushi Fujita12Kohei Hamanaka13Yuri Uchiyama14Naomi Tsuchida15Noriko Miyake16Kazuharu Misawa17Takeshi Mizuguchi18Satoko Miyatake19Naomichi Matsumoto20Department of Human Genetics, Yokohama City University Graduate School of MedicineBrain Research Institute, Niigata UniversityBrain Research Institute, Niigata UniversitySchool of Life Science and Technology, Tokyo Institute of TechnologySchool of Life Science and Technology, Tokyo Institute of TechnologyBiomedical Research Institute, National Institute of Advanced Industrial Science and Technology (AIST)Children’s Medical Center, Yokohama City University Medical CenterDepartment of Pediatric Cardiology, Yokohama City University HospitalDepartment of Pediatrics, Fujisawa City HospitalDepartment of Medical Genetics, Osaka Women’s and Children’s HospitalDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Research Institute, National Center for Global Health and MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineDepartment of Human Genetics, Yokohama City University Graduate School of MedicineAbstract The Drosophila behavior/human splicing protein family is involved in numerous steps of gene regulation. In humans, this family consists of three proteins: SFPQ, PSPC1, and NONO. Hemizygous loss-of-function (LoF) variants in NONO cause a developmental delay with several complications (e.g., distinctive facial features, cardiac symptoms, and skeletal symptoms) in an X-linked recessive manner. Most of the reported variants have been LoF variants, and two missense variants have been reported as likely deleterious but with no functional validation. We report three individuals from two families harboring an identical missense variant that is located in the nuclear localization signal, NONO: NM_001145408.2:c.1375C > G p.(Pro459Ala). All of them were male and the variant was inherited from their asymptomatic mothers. Individual 1 was diagnosed with developmental delay and cardiac phenotypes (ventricular tachycardia and dilated cardiomyopathy), which overlapped with the features of reported individuals having NONO LoF variants. Individuals 2 and 3 were monozygotic twins. Unlike in Individual 1, developmental delay with autistic features was the only symptom found in them. A fly experiment and cell localization experiment showed that the NONO variant impaired its proper intranuclear localization, leading to mild LoF. Our findings suggest that deleterious NONO missense variants should be taken into consideration when whole-exome sequencing is performed on male individuals with developmental delay with or without cardiac symptoms.https://doi.org/10.1038/s41598-023-27770-6 |
| spellingShingle | Toshiyuki Itai Atsushi Sugie Yohei Nitta Ryuto Maki Takashi Suzuki Yoichi Shinkai Yoshihiro Watanabe Yusuke Nakano Kazushi Ichikawa Nobuhiko Okamoto Yasuhiro Utsuno Eriko Koshimizu Atsushi Fujita Kohei Hamanaka Yuri Uchiyama Naomi Tsuchida Noriko Miyake Kazuharu Misawa Takeshi Mizuguchi Satoko Miyatake Naomichi Matsumoto A novel NONO variant that causes developmental delay and cardiac phenotypes Scientific Reports |
| title | A novel NONO variant that causes developmental delay and cardiac phenotypes |
| title_full | A novel NONO variant that causes developmental delay and cardiac phenotypes |
| title_fullStr | A novel NONO variant that causes developmental delay and cardiac phenotypes |
| title_full_unstemmed | A novel NONO variant that causes developmental delay and cardiac phenotypes |
| title_short | A novel NONO variant that causes developmental delay and cardiac phenotypes |
| title_sort | novel nono variant that causes developmental delay and cardiac phenotypes |
| url | https://doi.org/10.1038/s41598-023-27770-6 |
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