A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans
The meiosis-specific LINC complex, composed of the KASH5 and SUN1 proteins, tethers the moving chromosomes to the nuclear envelope to facilitate homolog pairing and is essential for gametogenesis. Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from r...
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Frontiers Media S.A.
2023-02-01
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| Series: | Frontiers in Endocrinology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fendo.2023.1128362/full |
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| author | Xiaoning Hou Xiaoning Hou Xiaoning Hou Xiaoning Hou Aurang Zeb Aurang Zeb Aurang Zeb Aurang Zeb Sobia Dil Sobia Dil Sobia Dil Sobia Dil Jianteng Zhou Jianteng Zhou Jianteng Zhou Jianteng Zhou Huan Zhang Huan Zhang Huan Zhang Huan Zhang Baolu Shi Baolu Shi Baolu Shi Baolu Shi Zubair Muhammad Zubair Muhammad Zubair Muhammad Zubair Muhammad Ihsan Khan Ihsan Khan Ihsan Khan Ihsan Khan Qamar Zaman Qamar Zaman Qamar Zaman Qamar Zaman Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Limin Wu Limin Wu Limin Wu Limin Wu Hui Ma Hui Ma Hui Ma Hui Ma Qinghua Shi Qinghua Shi Qinghua Shi Qinghua Shi |
| author_facet | Xiaoning Hou Xiaoning Hou Xiaoning Hou Xiaoning Hou Aurang Zeb Aurang Zeb Aurang Zeb Aurang Zeb Sobia Dil Sobia Dil Sobia Dil Sobia Dil Jianteng Zhou Jianteng Zhou Jianteng Zhou Jianteng Zhou Huan Zhang Huan Zhang Huan Zhang Huan Zhang Baolu Shi Baolu Shi Baolu Shi Baolu Shi Zubair Muhammad Zubair Muhammad Zubair Muhammad Zubair Muhammad Ihsan Khan Ihsan Khan Ihsan Khan Ihsan Khan Qamar Zaman Qamar Zaman Qamar Zaman Qamar Zaman Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Limin Wu Limin Wu Limin Wu Limin Wu Hui Ma Hui Ma Hui Ma Hui Ma Qinghua Shi Qinghua Shi Qinghua Shi Qinghua Shi |
| author_sort | Xiaoning Hou |
| collection | DOAJ |
| description | The meiosis-specific LINC complex, composed of the KASH5 and SUN1 proteins, tethers the moving chromosomes to the nuclear envelope to facilitate homolog pairing and is essential for gametogenesis. Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from reproductive failure, and identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20). This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother. The four sisters displayed diminished ovarian reserve (DOR), with one sister never being pregnant but still having dominant follicle at 35 years old and three sisters suffering from at least 3 miscarriages occurring within the third month of gestation. The truncated KASH5 mutant protein, when expressed in cultured cells, displays a similar localization encircling the nucleus and a weakened interaction with SUN1, as compared with the full-length KASH5 proteins, which provides a potential explanation for the phenotypes in the affected females. This study reported sexual dimorphism for influence of the KASH5 mutation on human germ cell development, and extends the clinical manifestations associated with KASH5 mutations, providing genetic basis for the molecular diagnosis of NOA, DOR, and recurrent miscarriage. |
| first_indexed | 2024-04-10T15:18:12Z |
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| id | doaj.art-4dce42a187ea4da8b7abf442c482b636 |
| institution | Directory Open Access Journal |
| issn | 1664-2392 |
| language | English |
| last_indexed | 2024-04-10T15:18:12Z |
| publishDate | 2023-02-01 |
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| series | Frontiers in Endocrinology |
| spelling | doaj.art-4dce42a187ea4da8b7abf442c482b6362023-02-14T17:09:15ZengFrontiers Media S.A.Frontiers in Endocrinology1664-23922023-02-011410.3389/fendo.2023.11283621128362A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humansXiaoning Hou0Xiaoning Hou1Xiaoning Hou2Xiaoning Hou3Aurang Zeb4Aurang Zeb5Aurang Zeb6Aurang Zeb7Sobia Dil8Sobia Dil9Sobia Dil10Sobia Dil11Jianteng Zhou12Jianteng Zhou13Jianteng Zhou14Jianteng Zhou15Huan Zhang16Huan Zhang17Huan Zhang18Huan Zhang19Baolu Shi20Baolu Shi21Baolu Shi22Baolu Shi23Zubair Muhammad24Zubair Muhammad25Zubair Muhammad26Zubair Muhammad27Ihsan Khan28Ihsan Khan29Ihsan Khan30Ihsan Khan31Qamar Zaman32Qamar Zaman33Qamar Zaman34Qamar Zaman35Wasim Akbar Shah36Wasim Akbar Shah37Wasim Akbar Shah38Wasim Akbar Shah39Xiaohua Jiang40Xiaohua Jiang41Xiaohua Jiang42Xiaohua Jiang43Limin Wu44Limin Wu45Limin Wu46Limin Wu47Hui Ma48Hui Ma49Hui Ma50Hui Ma51Qinghua Shi52Qinghua Shi53Qinghua Shi54Qinghua Shi55The First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe First Affiliated Hospital of University of Science and Technology of China, Hefei, ChinaSchool of Basic Medical Sciences, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, ChinaBiomedical Sciences and Health Laboratory of Anhui Province, Hefei, ChinaInstitute of Health and Medicine, Hefei Comprehensive National Science Center, Hefei, ChinaThe meiosis-specific LINC complex, composed of the KASH5 and SUN1 proteins, tethers the moving chromosomes to the nuclear envelope to facilitate homolog pairing and is essential for gametogenesis. Here, we applied whole-exome sequencing for a consanguineous family with five siblings suffering from reproductive failure, and identified a homozygous frameshift mutation in KASH5 (c.1270_1273del, p.Arg424Thrfs*20). This mutation leads to the absence of KASH5 protein expression in testes and non-obstructive azoospermia (NOA) due to meiotic arrest before the pachytene stage in the affected brother. The four sisters displayed diminished ovarian reserve (DOR), with one sister never being pregnant but still having dominant follicle at 35 years old and three sisters suffering from at least 3 miscarriages occurring within the third month of gestation. The truncated KASH5 mutant protein, when expressed in cultured cells, displays a similar localization encircling the nucleus and a weakened interaction with SUN1, as compared with the full-length KASH5 proteins, which provides a potential explanation for the phenotypes in the affected females. This study reported sexual dimorphism for influence of the KASH5 mutation on human germ cell development, and extends the clinical manifestations associated with KASH5 mutations, providing genetic basis for the molecular diagnosis of NOA, DOR, and recurrent miscarriage.https://www.frontiersin.org/articles/10.3389/fendo.2023.1128362/fullLINC complexKASH5meiotic arrestdiminished ovarian reserve (DOR)non-obstructive azoospermia (NOA)recurrent miscarriage (RM) |
| spellingShingle | Xiaoning Hou Xiaoning Hou Xiaoning Hou Xiaoning Hou Aurang Zeb Aurang Zeb Aurang Zeb Aurang Zeb Sobia Dil Sobia Dil Sobia Dil Sobia Dil Jianteng Zhou Jianteng Zhou Jianteng Zhou Jianteng Zhou Huan Zhang Huan Zhang Huan Zhang Huan Zhang Baolu Shi Baolu Shi Baolu Shi Baolu Shi Zubair Muhammad Zubair Muhammad Zubair Muhammad Zubair Muhammad Ihsan Khan Ihsan Khan Ihsan Khan Ihsan Khan Qamar Zaman Qamar Zaman Qamar Zaman Qamar Zaman Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Wasim Akbar Shah Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Xiaohua Jiang Limin Wu Limin Wu Limin Wu Limin Wu Hui Ma Hui Ma Hui Ma Hui Ma Qinghua Shi Qinghua Shi Qinghua Shi Qinghua Shi A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans Frontiers in Endocrinology LINC complex KASH5 meiotic arrest diminished ovarian reserve (DOR) non-obstructive azoospermia (NOA) recurrent miscarriage (RM) |
| title | A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans |
| title_full | A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans |
| title_fullStr | A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans |
| title_full_unstemmed | A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans |
| title_short | A homozygous KASH5 frameshift mutation causes diminished ovarian reserve, recurrent miscarriage, and non-obstructive azoospermia in humans |
| title_sort | homozygous kash5 frameshift mutation causes diminished ovarian reserve recurrent miscarriage and non obstructive azoospermia in humans |
| topic | LINC complex KASH5 meiotic arrest diminished ovarian reserve (DOR) non-obstructive azoospermia (NOA) recurrent miscarriage (RM) |
| url | https://www.frontiersin.org/articles/10.3389/fendo.2023.1128362/full |
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