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 counselling 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.

中文翻译：

---

纯合 GRN 突变：新的表型和对病理和分子机制的新见解。

颗粒蛋白原基因 (GRN) 中的纯合突变与神经元蜡样脂褐质沉积症 11 (CLN11) 相关，这是一种罕见的溶酶体储存障碍，其特征是小脑共济失调、癫痫、视网膜色素变性和认知障碍，通常在 13 至 25 岁之间开始。这是一种罕见的情况，以前仅在四个家庭中报道过。相比之下，杂合 GRN 突变是与神经元胞质 TDP-43 内含物相关的额颞叶痴呆的主要原因。我们在六名新患者中发现了纯合 GRN 突变。表型谱比以前报道的要广泛得多，有两种明显不同的表现，具体取决于发病年龄。儿童/青少年型的特征是在早期发病时出现经典的 CLN11 症状。不料，其他纯合子患者在 50 年后出现明显的额颞叶痴呆和帕金森病延迟表型；没有人患有癫痫症或小脑性共济失调。这项研究的另一个主要发现是，所有 GRN 突变对颗粒蛋白前体蛋白合成的影响可能不同。在一个具有纯合剪接位点突变和迟发性额颞叶痴呆的病例中检测到血浆颗粒蛋白前体残留水平和低水平正常转录物的存在，支持了一些突变的亚形效应。这是一项新的重要发现，必须在基于替代策略的治疗试验中加以考虑。首次对纯合子携带者进行的神经病理学研究为该疾病的病理机制提供了新的见解。存在神经元蜡样脂褐质沉积症的标志。TDP-43 细胞质内含物的缺失与杂合突变的观察明显不同，这表明溶酶体和 TDP-43 病理之间的病理转变取决于单或双等位基因状态。一个有趣的观察是一些神经元细胞核中正常 TDP-43 染色的丧失，这可能是 TDP-43 病理过程的第一阶段，在典型的细胞质包涵体形成之前。最后，这项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该向 CLN11 患者的孩子和父母提供特定的遗传咨询，因为他们是患痴呆症的高风险的杂合子携带者。更广泛地，