Unit of Molecular Neurogenetics, The Foundation 'Carlo Besta' Institute of Neurology, Milan, Italy.
Nat Genet. 2011 Mar;43(3):259-63. doi: 10.1038/ng.761. Epub 2011 Jan 30.
Although mutations in CYTB (cytochrome b) or BCS1L have been reported in isolated defects of mitochondrial respiratory chain complex III (cIII), most cIII-defective individuals remain genetically undefined. We identified a homozygous nonsense mutation in the gene encoding tetratricopeptide 19 (TTC19) in individuals from two families affected by progressive encephalopathy associated with profound cIII deficiency and accumulation of cIII-specific assembly intermediates. We later found a second homozygous nonsense mutation in a fourth affected individual. We demonstrated that TTC19 is embedded in the inner mitochondrial membrane as part of two high-molecular-weight complexes, one of which coincides with cIII. We then showed a physical interaction between TTC19 and cIII by coimmunoprecipitation. We also investigated a Drosophila melanogaster knockout model for TTC19 that showed low fertility, adult-onset locomotor impairment and bang sensitivity, associated with cIII deficiency. TTC19 is a putative cIII assembly factor whose disruption is associated with severe neurological abnormalities in humans and flies.
虽然已经报道了 CYTB（细胞色素 b）或 BCS1L 基因中的突变与线粒体呼吸链复合物 III（cIII）的孤立缺陷有关，但大多数 cIII 缺陷个体的遗传仍未明确。我们在两个受渐进性脑病影响的家族中发现了编码四肽重复蛋白 19（TTC19）的基因的纯合无义突变，这些家族的个体存在严重的 cIII 缺陷和 cIII 特异性组装中间体的积累。后来，我们在第四个受影响的个体中发现了第二个纯合无义突变。我们证明 TTC19 作为两个高分子量复合物的一部分嵌入在内线粒体膜中，其中一个复合物与 cIII 重合。我们通过共免疫沉淀显示了 TTC19 和 cIII 之间的物理相互作用。我们还研究了一种果蝇 TTC19 敲除模型，该模型表现出低生育力、成年发病的运动障碍和对 bang 敏感，与 cIII 缺陷有关。TTC19 是一种假定的 cIII 组装因子，其缺失与人类和果蝇的严重神经异常有关。
