Department of Medical Genetics, Oslo University Hospital and University of Oslo, Oslo, Norway.
Division of Pediatric and Adolescent Medicine, Division of Pediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway.
Brain. 2022 Jul 29;145(7):2602-2616. doi: 10.1093/brain/awac034.
Bi-allelic pathogenic variants in ZBTB11 have been associated with intellectual developmental disorder, autosomal recessive 69 (MRT69; OMIM 618383). We report five patients from three families with novel, bi-allelic variants in ZBTB11. We have expanded the clinical phenotype of MRT69, documenting varied severity of atrophy affecting different brain regions and described combined malonic and methylmalonic aciduria as a biochemical manifestation. As ZBTB11 encodes for a transcriptional regulator, we performeded chromatin immunoprecipitation-sequencing targeting ZBTB11 in fibroblasts from patients and controls. Chromatin immunoprecipitation-sequencing revealed binding of wild-type ZBTB11 to promoters in 238 genes, among which genes encoding proteins involved in mitochondrial functions and RNA processing are over-represented. Mutated ZBTB11 showed reduced binding to 61 of the targeted genes, indicating that the variants act as loss of function. Most of these genes are related to mitochondrial functions. Transcriptome analysis of the patient fibroblasts revealed dysregulation of mitochondrial functions. In addition, we uncovered that reduced binding of the mutated ZBTB11 to ACSF3 leads to decreased ACSF3 transcript level, explaining combined malonic and methylmalonic aciduria. Collectively, these results expand the clinical spectrum of ZBTB11-related neurological disease and give insight into the pathophysiology in which the dysfunctional ZBTB11 affect mitochondrial functions and RNA processing contributing to the neurological and biochemical phenotypes.
ZBTB11 的双等位致病性变异与智力发育障碍、常染色体隐性 69 型（MRT69；OMIM 618383）有关。我们报道了来自三个家庭的五名患者，他们携带 ZBTB11 的新的双等位变异。我们扩展了 MRT69 的临床表型，记录了不同严重程度的萎缩影响不同的脑区，并描述了丙二酸和甲基丙二酸尿症的联合表现为生化表现。由于 ZBTB11 编码转录调节剂，我们在患者和对照的成纤维细胞中进行了针对 ZBTB11 的染色质免疫沉淀测序。染色质免疫沉淀测序显示野生型 ZBTB11 与 238 个基因的启动子结合，其中编码涉及线粒体功能和 RNA 处理的蛋白质的基因过表达。突变型 ZBTB11 显示对 61 个靶向基因的结合减少，表明这些变体作为功能丧失起作用。这些基因大多数与线粒体功能有关。患者成纤维细胞的转录组分析显示线粒体功能失调。此外，我们发现突变型 ZBTB11 与 ACSF3 的结合减少导致 ACSF3 转录本水平降低，解释了丙二酸和甲基丙二酸尿症的联合发生。总的来说，这些结果扩展了 ZBTB11 相关神经疾病的临床谱，并深入了解了功能失调的 ZBTB11 影响线粒体功能和 RNA 处理的病理生理学，从而导致神经和生化表型。
