纯合子GRN突变：意外的表型和对病理和分子机制的新认识
Homozygous GRN mutations: unexpected phenotypes and new insights into pathological and molecular mechanisms
摘要：
颗粒蛋白前体基因（GRN）的纯合突变与神经元蜡样质脂褐质沉积症11（CLN 11）相关，CLN 11是一种罕见的溶酶体沉积症，其特征为小脑共济失调、癫痫发作、色素性视网膜炎和认知障碍，通常在13至25岁之间开始。这是一种罕见的疾病，以前只在四个家庭中报道过。相反，杂合GRN突变是与神经元胞质TDP-43包涵体相关的额颞叶痴呆的主要原因。我们在6名新患者中发现了纯合GRN突变。表型谱比以前报道的要宽得多，根据发病年龄有两种明显不同的表现。儿童/青少年形式的特征在于在发病时的早期典型CLN 11症状。出乎意料的是，其他纯合子患者在50年后出现了明显的额颞叶痴呆和帕金森综合征的延迟表型;没有癫痫或小脑共济失调。这项研究的另一个主要发现是，所有GRN突变可能对颗粒蛋白前体蛋白合成的影响不同。在一例纯合剪接位点突变和晚发性额颞叶痴呆患者中检测到血浆颗粒蛋白前体残留水平和正常转录物低水平，这支持了某些突变的亚型效应。这是一个新的关键发现，必须在基于替代策略的治疗试验中加以考虑。在纯合子携带者中进行的第一项神经病理学研究为该疾病的病理机制提供了新的见解。存在神经元蜡样质脂褐质沉积症的特征。TDP-43胞质内含物的缺乏与杂合突变的观察结果明显不同，表明溶酶体和TDP-43病理之间的病理转变取决于单或双等位基因状态。一个有趣的观察是在一些神经元的细胞核中正常TDP-43染色的损失，这可能是在形成典型的细胞质内含物之前TDP-43病理过程的第一阶段。最后，本研究对遗传咨询和分子诊断具有重要意义。GRN突变的半显性遗传意味着应向CLN 11患者的儿童和父母提供特定的遗传咨询，因为他们是杂合子携带者，患痴呆症的风险很高。更广泛地说，这项研究表明，遗传变异可以根据其单或双等位基因状态导致不同的表型，这对遗传诊断是一个挑战。
英文摘要：
Homozygous mutations in the progranulin gene (GRN) are associated with neuronal ceroid lipofuscinosis 11 (CLN11), a rare lysosomal-storage disorder characterized by cerebellar ataxia, seizures, retinitis pigmentosa, and cognitive disorders, usually beginning between 13 and 25 years of age. This is a rare condition, previously reported in only four families. In contrast, heterozygous GRN mutations are a major cause of frontotemporal dementia associated with neuronal cytoplasmic TDP-43 inclusions. We identified homozygous GRN mutations in six new patients. The phenotypic spectrum is much broader than previously reported, with two remarkably distinct presentations, depending on the age of onset. A childhood/juvenile form is characterized by classical CLN11 symptoms at an early age at onset. Unexpectedly, other homozygous patients presented a distinct delayed phenotype of frontotemporal dementia and parkinsonism after 50 years; none had epilepsy or cerebellar ataxia. Another major finding of this study is that all GRN mutations may not have the same impact on progranulin protein synthesis. A hypomorphic effect of some mutations is supported by the presence of residual levels of plasma progranulin and low levels of normal transcript detected in one case with a homozygous splice-site mutation and late onset frontotemporal dementia. This is a new critical finding that must be considered in therapeutic trials based on replacement strategies. The first neuropathological study in a homozygous carrier provides new insights into the pathological mechanisms of the disease. Hallmarks of neuronal ceroid lipofuscinosis were present. The absence of TDP-43 cytoplasmic inclusions markedly differs from observations of heterozygous mutations, suggesting a pathological shift between lysosomal and TDP-43 pathologies depending on the mono or bi-allelic status. An intriguing observation was the loss of normal TDP-43 staining in the nucleus of some neurons, which could be the first stage of the TDP-43 pathological process preceding the formation of typical cytoplasmic inclusions. Finally, this study has important implications for genetic counselling and molecular diagnosis. Semi-dominant inheritance of GRN mutations implies that specific genetic counseling should be delivered to children and parents of CLN11 patients, as they are heterozygous carriers with a high risk of developing dementia. More broadly, this study illustrates the fact that genetic variants can lead to different phenotypes according to their mono- or bi-allelic state, which is a challenge for genetic diagnosis.
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