Mutation of FLNA attenuating the migration of abdominal muscles contributed to Melnick-Needles syndrome (MNS) in a family with recurrent miscarriage

作者全名："Luo, Xin; Yang, Zailin; Zeng, Jing; Chen, Jing; Chen, Ningxuan; Jiang, Xiaoyan; Wei, Qinlv; Yi, Ping; Xu, Jing"

作者地址："[Luo, Xin; Chen, Jing; Chen, Ningxuan; Jiang, Xiaoyan; Wei, Qinlv; Yi, Ping; Xu, Jing] Chongqing Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Yang, Zailin] Chongqing Univ, Canc Hosp, Chongqing, Peoples R China; [Zeng, Jing] Yubei Dist Chinese Med Hosp, Dept Obstet & Gynecol, Chongqing, Peoples R China; [Yi, Ping; Xu, Jing] Chongqing Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Chongqing 401120, Peoples R China"

通信作者："Yi, P; Xu, J (通讯作者)，Chongqing Med Univ, Affiliated Hosp 3, Dept Obstet & Gynecol, Chongqing 401120, Peoples R China."

来源：MOLECULAR GENETICS & GENOMIC MEDICINE

ESI学科分类：MOLECULAR BIOLOGY & GENETICS

WOS号：WOS:000922420800001

JCR分区：Q4

影响因子：1.5

年份：2023

卷号：　

期号：　

开始页：　

结束页：　

文献类型：Article; Early Access

关键词：FLNA; Melnick-Needles syndrome; midline structure dysplasia; recurrent miscarriage

摘要："BackgroundFilamin 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. MethodsWe 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. ResultsThe 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. ConclusionOur 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."

基金机构：Chongqing Science and Health Joint Medical Research Project [2019ZDXM030]; Chongqing Overseas Chinese Returned Entrepreneurship and Innovation Support Plan [cx2020093]; Scientific Research Incubation Project of the Third Affiliated Hospital of Chongqing Medical University [KY08030]

基金资助正文："ACKNOWLEDGMENTS The authors would like to thank the families who took part in this research. This research was supported by Chongqing Science and Health Joint Medical Research Project (2019ZDXM030), Chongqing Overseas Chinese Returned Entrepreneurship and Innovation Support Plan (cx2020093), and the Scientific Research Incubation Project of the Third Affiliated Hospital of Chongqing Medical University (KY08030)."