Department of Biology, Molecular Embryology, Philipps-University Marburg, 35043 Marburg, Germany.
Institute of Human Genetics, University Medical Center Göttingen, 37073 Göttingen, Germany.
Dis Model Mech. 2024 Jun 1;17(6). doi: 10.1242/dmm.050507. Epub 2024 May 14.
De novo truncating variants in fibrosin-like 1 (FBRSL1), a member of the AUTS2 gene family, cause a disability syndrome, including organ malformations such as heart defects. Here, we use Xenopus laevis to investigate whether Fbrsl1 plays a role in heart development. Xenopus laevis fbrsl1 is expressed in tissues relevant for heart development, and morpholino-mediated knockdown of Fbrsl1 results in severely hypoplastic hearts. Our data suggest that Fbrsl1 is required for the development of the first heart field, which contributes to the ventricle and the atria, but not for the second heart field, which gives rise to the outflow tract. The morphant heart phenotype could be rescued using a human N-terminal FBRSL1 isoform that contains an alternative exon, but lacks the AUTS2 domain. N-terminal isoforms carrying patient variants failed to rescue. Interestingly, a long human FBRSL1 isoform, harboring the AUTS2 domain, also did not rescue the morphant heart defects. Thus, our data suggest that different FBRSL1 isoforms may have distinct functions and that only the short N-terminal isoform, appears to be critical for heart development.
纤维连接蛋白样 1（FBRSL1）中的从头截短变异体，是 AUTS2 基因家族的成员，可引起一种残疾综合征，包括心脏缺陷等器官畸形。在这里，我们使用非洲爪蟾来研究 Fbrsl1 是否在心脏发育中发挥作用。非洲爪蟾 fbrsl1 在与心脏发育相关的组织中表达，而通过 morpholino 介导的 Fbrsl1 敲低会导致心脏严重发育不良。我们的数据表明，Fbrsl1 对于第一心脏场的发育是必需的，该场有助于心室和心房的发育，但对于第二心脏场的发育不是必需的，第二心脏场形成流出道。使用包含替代外显子但缺乏 AUTS2 结构域的人类 N 端 FBRSL1 异构体可以挽救形态发生的心表型。携带患者变异体的 N 端异构体不能挽救。有趣的是，具有 AUTS2 结构域的长人类 FBRSL1 异构体也不能挽救形态发生的心缺陷。因此，我们的数据表明，不同的 FBRSL1 异构体可能具有不同的功能，只有短的 N 端异构体似乎对心脏发育至关重要。
