Heterozygous loss-of-function (LOF) mutations in the human progranulin gene (GRN) cause frontotemporal lobar degeneration (FTLD) by a mechanism of haploinsufficiency. Patients present most frequently with frontotemporal dementia, which is the second most common neurodegenerative dementia at young age. Currently, no disease-modifying therapies are available for these patients. Stimulating GRN protein expression or inhibiting its breakdown is an obvious therapeutic strategy, and is indeed the focus of current preclinical research and clinical trials. Multiple studies have demonstrated the heterogeneity in clinical presentation and wide variability in age of onset in patients carrying a GRN LOF mutation. Recently, this heterogeneity became an opportunity to identify disease modifiers, considering that these might constitute suitable targets for developing disease-modifying or disease-delaying therapies.

人类前颗粒蛋白基因（GRN）中的杂合功能丧失（LOF）突变通过单倍体机能不全的机制引起额颞叶变性（FTLD）。患者最常出现额颞痴呆，这是年轻时第二常见的神经退行性痴呆。当前，没有针对这些患者的改善疾病的疗法。刺激GRN蛋白表达或抑制其降解是一种明显的治疗策略，并且确实是当前临床前研究和临床试验的重点。多项研究表明，携带GRN的患者在临床表现上存在异质性，且发病年龄差异很大LOF突变。近来，这种异质性成为鉴定疾病改良剂的机会，考虑到它们可能构成开发疾病改良或延缓疾病疗法的合适靶标。