A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family
Abstract 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 under...
Saved in:
| Main Authors: | , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
BMC
2025-03-01
|
| Series: | European Journal of Medical Research |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s40001-025-02418-5 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849761999254192128 |
|---|---|
| author | Mingrong Xia Chenhao Gao Junkui Shang Dan Li Ali Yang Weizhou Zang Jiewen Zhang |
| author_facet | Mingrong Xia Chenhao Gao Junkui Shang Dan Li Ali Yang Weizhou Zang Jiewen Zhang |
| author_sort | Mingrong Xia |
| collection | DOAJ |
| description | Abstract 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. Methods 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. Results 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. Conclusions 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. |
| format | Article |
| id | doaj-art-9ab6bacabed04bb48fb5be8cfed459ac |
| institution | DOAJ |
| issn | 2047-783X |
| language | English |
| publishDate | 2025-03-01 |
| publisher | BMC |
| record_format | Article |
| series | European Journal of Medical Research |
| spelling | doaj-art-9ab6bacabed04bb48fb5be8cfed459ac2025-08-20T03:05:52ZengBMCEuropean Journal of Medical Research2047-783X2025-03-0130111110.1186/s40001-025-02418-5A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han familyMingrong Xia0Chenhao Gao1Junkui Shang2Dan Li3Ali Yang4Weizhou Zang5Jiewen Zhang6Department of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalDepartment of Neurology, Henan Provincial People’s Hospital, Zhengzhou University People’s HospitalAbstract 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. Methods 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. Results 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. Conclusions 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.https://doi.org/10.1186/s40001-025-02418-5Alzheimer’s diseaseProgranulinGRNV490M mutationFrontotemporal dementia |
| spellingShingle | Mingrong Xia Chenhao Gao Junkui Shang Dan Li Ali Yang Weizhou Zang Jiewen Zhang A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family European Journal of Medical Research Alzheimer’s disease Progranulin GRN V490M mutation Frontotemporal dementia |
| title | A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family |
| title_full | A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family |
| title_fullStr | A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family |
| title_full_unstemmed | A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family |
| title_short | A novel c.1468 G > A GRN mutation causes frontotemporal dementia in a Chinese Han family |
| title_sort | novel c 1468 g a grn mutation causes frontotemporal dementia in a chinese han family |
| topic | Alzheimer’s disease Progranulin GRN V490M mutation Frontotemporal dementia |
| url | https://doi.org/10.1186/s40001-025-02418-5 |
| work_keys_str_mv | AT mingrongxia anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT chenhaogao anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT junkuishang anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT danli anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT aliyang anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT weizhouzang anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT jiewenzhang anovelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT mingrongxia novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT chenhaogao novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT junkuishang novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT danli novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT aliyang novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT weizhouzang novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily AT jiewenzhang novelc1468gagrnmutationcausesfrontotemporaldementiainachinesehanfamily |