Xia Mingrong, Gao Chenhao, Shang Junkui, Li Dan, Yang Ali, Zang Weizhou, Zhang Jiewen
Department of Neurology, Henan Provincial People's Hospital, Zhengzhou University People's Hospital, Zhengzhou, 450003, Henan, China.
Academy of Medical Sciences, Zhengzhou University, Zhengzhou, 450003, Henan, China.
Eur J Med Res. 2025 Mar 8;30(1):157. doi: 10.1186/s40001-025-02418-5.
BACKGROUND/PURPOSE: GRN mutations act as causative factors in patients with FTD clinical phenotype or FTD pathology and exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with resembling Alzheimer's disease should be critical to understand the pathogenesis of FTD.
Clinical analysis, neuroimaging, target region capture and high-throughput sequencing were performed in a family of 3 generations. The underlying Alzheimer's pathology was evaluated by using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing, 18F-florbetapir (AV-45) PET imaging and FDG18-positron emission tomography imaging.
Through target region capture and high-throughput sequencing, a three-generation family was able to identify a heterozygous G to A point mutation at position 490 (c.1468)G > A, which led to a valine to methionine substitution (V490M) at exon 12. This unique missense mutation was found at codon 1468. Eight members of the proband's family-two sisters and the proband himself-had the mutation found by Sanger sequencing. Interestingly, biomarker tests for amyloid in the proband's cerebrospinal fluid (CSF) indicated pathology consistent with Alzheimer's disease (AD). The mutation was expected to have a high likelihood of being pathogenic.
We firstly reported a novel mutation in the GRN gene at codon 490 (V490M) in exon 12 in a China FTD family. The CSF biomarker alterations of the proband revealed a reduction in Aβ42 and the Aβ42/Aβ40 ratio. The analysis of mutation might support the role of GRN in patients with FTD and contribute to the discovery of a new pathological mechanism underlying the disease.
背景/目的：GRN突变是具有额颞叶痴呆（FTD）临床表型或FTD病理特征患者的致病因素，且表现出高度的临床异质性。发现这些突变并分析它们与类似阿尔茨海默病的关联对于理解FTD的发病机制至关重要。
对一个三代家系进行了临床分析、神经影像学检查、目标区域捕获和高通量测序。通过脑脊液（CSF）淀粉样蛋白检测、18F-氟比他派（AV-45）PET成像和FDG18-正电子发射断层扫描成像获得的生物标志物证据评估潜在的阿尔茨海默病病理。
通过目标区域捕获和高通量测序，一个三代家系鉴定出第490位（c.1468）的杂合G到A点突变，导致第12外显子缬氨酸到甲硫氨酸的替代（V490M）。这个独特的错义突变位于密码子1468。先证者家族的八名成员——两名姐妹和先证者本人——通过桑格测序发现携带该突变。有趣的是，先证者脑脊液（CSF）中的淀粉样蛋白生物标志物检测表明其病理与阿尔茨海默病（AD）一致。该突变很可能具有致病性。
我们首次报道了一个中国FTD家系中GRN基因第12外显子密码子490（V490M）的新突变。先证者的脑脊液生物标志物改变显示Aβ42及Aβ42/Aβ40比值降低。对该突变的分析可能支持GRN在FTD患者中的作用，并有助于发现该疾病潜在的新病理机制。
