Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage
Abstract Background Filamin A, encoded by the X‐linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick–Needles syndrome (MN...
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| Format: | Article |
| Language: | English |
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Wiley
2023-05-01
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| Series: | Molecular Genetics & Genomic Medicine |
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| Online Access: | https://doi.org/10.1002/mgg3.2145 |
| _version_ | 1797828614777995264 |
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| author | Xin Luo Zailin Yang Jing Zeng Jing Chen Ningxuan Chen Xiaoyan Jiang Qinlv Wei Ping Yi Jing Xu |
| author_facet | Xin Luo Zailin Yang Jing Zeng Jing Chen Ningxuan Chen Xiaoyan Jiang Qinlv Wei Ping Yi Jing Xu |
| author_sort | Xin Luo |
| collection | DOAJ |
| description | Abstract Background Filamin A, encoded by the X‐linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick–Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood. Methods We found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas‐mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay. Results The first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of the FLNA gene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild‐type FLNA. These FLNA‐mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutated FLNA. Finally, we summarized the cases of MNS with FLNA mutation from the accessible published literature thus far. Conclusion Our research revealed a mutation site of the FLNA for MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders. |
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| id | doaj.art-9fc98b08bef9420cb732a30a34d9a7a7 |
| institution | Directory Open Access Journal |
| issn | 2324-9269 |
| language | English |
| last_indexed | 2024-04-09T13:07:10Z |
| publishDate | 2023-05-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Genetics & Genomic Medicine |
| spelling | doaj.art-9fc98b08bef9420cb732a30a34d9a7a72023-05-12T14:52:44ZengWileyMolecular Genetics & Genomic Medicine2324-92692023-05-01115n/an/a10.1002/mgg3.2145Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriageXin Luo0Zailin Yang1Jing Zeng2Jing Chen3Ningxuan Chen4Xiaoyan Jiang5Qinlv Wei6Ping Yi7Jing Xu8Department of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaChongqing University Cancer Hospital Chongqing ChinaDepartment of Obstetrics and Gynecology Yubei District Chinese Medicine Hospital Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaDepartment of Obstetrics and Gynecology The Third Affiliated Hospital of Chongqing Medical University Chongqing ChinaAbstract Background Filamin A, encoded by the X‐linked gene FLNA, links the cell membrane with the cytoskeleton and acts as a regulator of the actin cytoskeleton. Mutations in FLNA cause a large spectrum of congenital malformations during embryonic development, including Melnick–Needles syndrome (MNS). However, reports of MNS, especially in males, are rare, and the pathogenesis molecular mechanisms are not well understood. Methods We found a family with two consecutive miscarriages of similar fetuses with multiple malformations. DNA was extracted from peripheral blood and tissues, and whole exome sequencing was performed for genetic analysis. Then, we created a C57BL/6 mouse with a point mutation by CRISPR/Cas‐mediated genome engineering. The migration of primary abdominal muscle cell was detected by wound healing assay. Results The first fetus showed congenital hygroma colli and omphalocele identified by ultrasound at 12 wks; the second fetus showed hygroma colli and thoraco abdominoschisis at 12 wks, with a new hemizygous mutation c.4420G>A in exon 26 of the FLNA gene, which is predicted to cause an amino acid substitution (p.Asp1474Asn). The mother and grandmother were both present in the c.4420G>A heterozygous state, and the mother's healthy brother had wild‐type FLNA. These FLNA‐mutated mice exhibited a broader central gap between the rectus abdominis than the wild type (WT), similar to the midline structure dysplasia of the abdominal wall in the two fetuses. Wound healing assays showed the attenuated migration capacity of abdominal muscle cells in mice with mutated FLNA. Finally, we summarized the cases of MNS with FLNA mutation from the accessible published literature thus far. Conclusion Our research revealed a mutation site of the FLNA for MNS and explored the mechanism of midline structure dysplasia in the abdominal wall of male patients, which could provide more evidence for the clinical diagnosis and genetic counseling of families with these disorders.https://doi.org/10.1002/mgg3.2145FLNAMelnick–Needles syndromemidline structure dysplasiarecurrent miscarriage |
| spellingShingle | Xin Luo Zailin Yang Jing Zeng Jing Chen Ningxuan Chen Xiaoyan Jiang Qinlv Wei Ping Yi Jing Xu Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage Molecular Genetics & Genomic Medicine FLNA Melnick–Needles syndrome midline structure dysplasia recurrent miscarriage |
| title | Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage |
| title_full | Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage |
| title_fullStr | Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage |
| title_full_unstemmed | Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage |
| title_short | Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick–Needles syndrome (MNS) in a family with recurrent miscarriage |
| title_sort | mutation of flna attenuating the migration of abdominal muscles contributed to melnick needles syndrome mns in a family with recurrent miscarriage |
| topic | FLNA Melnick–Needles syndrome midline structure dysplasia recurrent miscarriage |
| url | https://doi.org/10.1002/mgg3.2145 |
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