{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T23:05:02Z","timestamp":1789772702750,"version":"4.0.1"},"reference-count":20,"publisher":"BMJ","issue":"11","funder":[{"DOI":"10.13039\/501100012166","name":"National Key Research and Development Program of China","doi-asserted-by":"publisher","award":["2023YFC2705504"],"award-info":[{"award-number":["2023YFC2705504"]}],"id":[{"id":"10.13039\/501100012166","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Science and Technology Innovation Program of Hunan Province","award":["2023RC3233"],"award-info":[{"award-number":["2023RC3233"]}]},{"name":"Scientific Research Foundation of Reproductive and Genetic Hospital of CITIC-XIANGYA","award":["YNXM-202202"],"award-info":[{"award-number":["YNXM-202202"]}]},{"DOI":"10.13039\/501100004735","name":"Natural Science Foundation of Hunan Province","doi-asserted-by":"publisher","award":["2024JJ2083"],"award-info":[{"award-number":["2024JJ2083"]}],"id":[{"id":"10.13039\/501100004735","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82371672"],"award-info":[{"award-number":["82371672"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bmj.com"],"crossmark-restriction":true},"short-container-title":["J Med Genet"],"accepted":{"date-parts":[[2024,8,22]]},"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>Recurrent preimplantation embryo developmental arrest (RPEA) is the most common phenotype in assisted reproductive technology treatment failure associated with identified genetic abnormalities. Currently known maternal genetic variants explain only a limited number of cases. Variants of the \u03b2-tubulin subunit gene, <jats:italic>TUBB8<\/jats:italic>, cause oocyte meiotic arrest and RPEA through a broad spectrum of spindle defects. In contrast, \u03b1-tubulin subunit genes are poorly studied in the context of preimplantation embryonic development.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>Whole exome sequencing was performed on the PREA cohort. Functional characterisations of the identified candidate disease-causing variants were validated using Sanger sequencing, bioinformatics, in vitro functional analyses and single-cell RNA-sequencing of arrested embryos.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>Four homozygous variants were identified in the PREA cohort: two of <jats:italic>TUBA1C<\/jats:italic> (p.Gln358Ter and p.Asp444Metfs*42) and two of <jats:italic>TUBA4A<\/jats:italic> (p.Arg339Cys and p.Tyr440Ter). These variants cause varying degrees of spindle assembly defects. Additionally, we characterised changes in the human arrested embryo transcriptome carrying <jats:italic>TUBA4A<\/jats:italic> variants, with a particular focus on spindle organisation, chromosome segregation and mRNA decay.<\/jats:p>\n               <\/jats:sec>\n               <jats:sec>\n                  <jats:title>Conclusion<\/jats:title>\n                  <jats:p>Our findings identified <jats:italic>TUBA1C<\/jats:italic> as a novel genetic marker and expanded the genetic and phenotypic spectrum of <jats:italic>TUBA4A<\/jats:italic> in female infertility and RPEA, which altogether highlighted the importance of \u03b1-tubulin isotypes in preimplantation embryonic development.<\/jats:p>\n               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