Department of Biology, Molecular Embryology, Philipps-University Marburg, Marburg, Germany.
DFG Research Training Group, Membrane Plasticity in Tissue Development and Remodeling, GRK 2213, Philipps-Universität Marburg, Marburg, Germany.
Dev Dyn. 2019 Jun;248(6):465-476. doi: 10.1002/dvdy.39. Epub 2019 May 1.
Kabuki syndrome is a haploinsufficient congenital multi-organ malformation syndrome, which frequently includes severe heart defects. Mutations in the histone H3K4 methyltransferase KMT2D have been identified as the main cause of Kabuki syndrome, however, the role of KMT2D in heart development remains to be characterized.
Here we analyze the function of Kmt2d at different stages of Xenopus heart development. Xenopus Kmt2d is ubiquitously expressed at early stages of cardiogenesis, with enrichment in the anterior region including the cardiac precursor cells. Morpholino-mediated knockdown of Kmt2d led to hypoplastic hearts lacking the three-chambered structure. Analyzing different stages of cardiogenesis revealed that development of the first and second heart fields as well as cardiac differentiation were severely affected by loss of Kmt2d function.
Kmt2d loss of function in Xenopus recapitulates the hypoplastic heart defects observed in Kabuki syndrome patients and shows that Kmt2d function is required for the establishment of the primary and secondary heart fields. Thus, Xenopus Kmt2d morphants can be a valuable tool to elucidate the etiology of the congenital heart defects associated with Kabuki syndrome.
歌舞伎综合征是一种单倍剂量不足的先天性多器官畸形综合征，常伴有严重的心脏缺陷。组蛋白 H3K4 甲基转移酶 KMT2D 的突变已被确定为歌舞伎综合征的主要原因，但 KMT2D 在心脏发育中的作用仍有待阐明。
在这里，我们分析了 Kmt2d 在非洲爪蟾心脏发育的不同阶段的功能。非洲爪蟾 Kmt2d 在心脏发生的早期阶段广泛表达，在前区域包括心脏前体细胞中富集。利用 morpholino 介导的 Kmt2d 敲低导致心脏发育不全，缺乏三室结构。分析心脏发生的不同阶段表明，第一和第二心脏场的发育以及心脏分化受到 Kmt2d 功能丧失的严重影响。
非洲爪蟾 Kmt2d 功能丧失可再现歌舞伎综合征患者中观察到的心脏发育不全缺陷，并表明 Kmt2d 功能对于建立初级和次级心脏场是必需的。因此，非洲爪蟾 Kmt2d 形态发生缺陷体可以成为阐明与歌舞伎综合征相关的先天性心脏缺陷病因的有价值的工具。
