Departamento de Química Biológica Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, IQUIBICEN-CONICET, Buenos Aires, Argentina.
Departamento de Fisiología, Biología Molecular y Celular, Facultad de Ciencias Exactas y Naturales, Instituto de Biociencias, Biotecnología y Biología Traslacional, iB3, Universidad de Buenos Aires, Buenos Aires, Argentina.
Hum Mutat. 2020 Jul;41(7):1187-1208. doi: 10.1002/humu.24030. Epub 2020 May 22.
NKX2-5 is a homeodomain transcription factor that plays a crucial role in heart development. It is the first gene where a single genetic variant (GV) was found to be associated with congenital heart diseases in humans. In this study, we carried out a comprehensive survey of NKX2-5 GVs to build a unified, curated, and updated compilation of all available GVs. We retrieved a total of 1,380 unique GVs. From these, 970 had information on their frequency in the general population and 143 have been linked to pathogenic phenotypes in humans. In vitro effect was ascertained for 38 GVs. The homeodomain had the biggest cluster of pathogenic variants in the protein: 49 GVs in 60 residues, 23 in its third α-helix, where 11 missense variants may affect protein-DNA interaction or the hydrophobic core. We also pinpointed the likely location of pathogenic GVs in four linear motifs. These analyses allowed us to assign a putative explanation for the effect of 90 GVs. This study pointed to reliable pathogenicity for GVs in helix 3 of the homeodomain and may broaden the scope of functional and structural studies that can be done to better understand the effect of GVs in NKX2-5 function.
NKX2-5 是一种同源域转录因子，在心脏发育中起着至关重要的作用。它是第一个被发现与人类先天性心脏病相关的单一基因变异（GV）的基因。在这项研究中，我们对 NKX2-5 的 GV 进行了全面调查，以建立一个统一的、经过精心整理和更新的所有可用 GV 的综合编译。我们总共检索到了 1380 个独特的 GV。其中，970 个有关于其在普通人群中频率的信息，143 个与人类的致病表型有关。我们对 38 个 GV 的体外效应进行了确认。该蛋白的同源域中存在最大的致病性变异簇：60 个残基中有 49 个 GV，第三个α-螺旋中有 23 个，其中 11 个错义变异可能影响蛋白-DNA 相互作用或疏水性核心。我们还在四个线性基序中确定了致病性 GV 的可能位置。这些分析使我们能够对 90 个 GV 的效应给出一个可能的解释。这项研究表明，同源域的螺旋 3 中的 GV 具有可靠的致病性，可能拓宽了可以进行的功能和结构研究的范围，以更好地理解 GV 在 NKX2-5 功能中的作用。
