Loss-of-function mutations in the gene encoding for the protein progranulin (PGRN), GRN, are one of the major genetic abnormalities involved in frontotemporal lobar degeneration. However, genetic variations, mainly missense, in GRN have also been linked to other neurodegenerative diseases. We found 12 different pathogenic/likely pathogenic variants in 21 patients identified in a cohort of Italian patients affected by various neurodegenerative disorders. We detected the p.Thr272SerfsTer10 as the most frequent, followed by the c.1179+3A>G variant. We characterized the clinical phenotype of 12 patients from 3 pedigrees carrying the c.1179+3A>G variant, demonstrated the pathogenicity of this mutation, and detected other rarer variants causing haploinsufficiency (p.Met1?, c.709-2A>T, p.Gly79AspfsTer39). Finally, by applying bioinformatics, neuropathological, and biochemical studies, we characterized 6 missense/synonymous variants (p.Asp94His, p.Gly117Asp, p.Ala266Pro, p.Val279Val, p.Arg298His, p.Ala505Gly), including 4 previously unreported. The designation of variants is crucial for genetic counseling and the enrollment of patients in clinical studies.

中文翻译：

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意大利神经退行性疾病患者新型颗粒蛋白前体基因变体的表征

编码颗粒蛋白前体 (PGRN) 的基因中的功能丧失突变 GRN 是涉及额颞叶变性的主要遗传异常之一。然而，GRN 中的遗传变异（主要是错义）也与其他神经退行性疾病有关。我们在受各种神经退行性疾病影响的意大利患者队列中发现了 21 名患者的 12 种不同的致病性/可能致病性变异。我们检测到 p.Thr272SerfsTer10 是最常见的，其次是 c.1179+3A>G 变体。我们对来自 3 个携带 c.1179+3A>G 变异的家系的 12 名患者的临床表型进行了表征，证明了该突变的致病性，并检测了导致单倍体不足的其他罕见变异（p.Met1?，c.709-2A>T， p.Gly79AspfsTer39）。最后，通过应用生物信息学，神经病理学和生化研究，我们表征了 6 个错义/同义变体（p.Asp94His、p.Gly117Asp、p.Ala266Pro、p.Val279Val、p.Arg298His、p.Ala505Gly），包括 4 个以前未报告的。变异的指定对于遗传咨询和临床研究中的患者登记至关重要。