含亮氨酸拉链-EF手的跨膜蛋白1(LETM1)编码线粒体内膜蛋白,具有控制线粒体体积和离子稳态的渗透调节功能。LETM1与人类疾病的推定关联最初是在Wolf-Hirschhorn综合征中提出的,一种由染色体4p16.3的从头单等位基因缺失引起的疾病,该区域包含LETM1。利用外显子组测序和国际基因匹配工作,我们已经从11个无关家庭中鉴定出18个患病个体,这些个体携带超罕见的双等位基因错义和功能丧失LETM1变异体,临床表现高度提示线粒体疾病.这些表现为主要是婴儿发作(14/18,78%)和可变进行性神经系统的频谱,新陈代谢,和畸形症状,加上与神经变性相关的多器官功能障碍。常见特征包括呼吸链复杂缺陷(100%),全球发育迟缓(94%),视神经萎缩(83%),感觉神经性听力损失(78%),和小脑共济失调(78%),其次是癫痫(67%),痉挛(53%),和肌病(50%)。其他特征包括双侧白内障(42%),心肌病(36%),糖尿病(27%)。为了更好地了解已鉴定的LETM1变体的致病机制,我们对线粒体K+/H+交换活性进行了生化和形态学研究,蛋白质,在先证根来源的成纤维细胞和肌肉以及酿酒酵母中的形状,是线粒体渗透调节的重要模式生物。我们的结果表明,双等位基因LETM1变体与线粒体K+外排缺陷相关,肿胀的线粒体基质结构,和重要的线粒体氧化磷酸化蛋白成分的损失,因此强调了LETM1变异体在神经和线粒体病理中引起的线粒体渗透调节的意义。
Leucine zipper-EF-hand containing transmembrane protein 1 (
LETM1) encodes an inner mitochondrial membrane protein with an osmoregulatory function controlling mitochondrial volume and ion homeostasis. The putative association of
LETM1 with a human disease was initially suggested in Wolf-Hirschhorn syndrome, a disorder that results from de novo monoallelic deletion of chromosome 4p16.3, a region encompassing
LETM1. Utilizing exome sequencing and international gene-matching efforts, we have identified 18 affected individuals from 11 unrelated families harboring ultra-rare bi-allelic missense and loss-of-function
LETM1 variants and clinical presentations highly suggestive of mitochondrial disease. These manifested as a spectrum of predominantly infantile-onset (14/18, 78%) and variably progressive neurological, metabolic, and dysmorphic symptoms, plus multiple organ dysfunction associated with neurodegeneration. The common features included respiratory chain complex deficiencies (100%), global developmental delay (94%), optic atrophy (83%), sensorineural hearing loss (78%), and cerebellar ataxia (78%) followed by epilepsy (67%), spasticity (53%), and myopathy (50%). Other features included bilateral cataracts (42%), cardiomyopathy (36%), and diabetes (27%). To better understand the pathogenic mechanism of the identified LETM1 variants, we performed biochemical and morphological studies on mitochondrial K+/H+ exchange activity, proteins, and shape in proband-derived fibroblasts and muscles and in Saccharomyces cerevisiae, which is an important model organism for mitochondrial osmotic regulation. Our results demonstrate that bi-allelic
LETM1 variants are associated with defective mitochondrial K+ efflux, swollen mitochondrial matrix structures, and loss of important mitochondrial oxidative phosphorylation protein components, thus highlighting the implication of perturbed mitochondrial osmoregulation caused by LETM1 variants in neurological and mitochondrial pathologies.