Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2023 Aug;11(8):e2222.
doi: 10.1002/mgg3.2222. Epub 2023 Jun 5.

A novel splice-site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review

Chang Li  1 , Ya Wen  1 , Mengqiu Zhao  2 , Yaye Wang  2 , Ping Li  1   2 , Liang Wang  1   2 , Shan Wang  1   2
Affiliations
Review

A novel splice-site mutation in CHMP2B associated with frontotemporal dementia: The first report from China and literature review

Chang Li et al. Mol Genet Genomic Med. 2023 Aug.

Abstract

Background: Frontotemporal dementia (FTD) has genetic heterogeneity, and the endosomal ESCRTIII-complex subunit CHMP2B variant is a rare cause of FTD. The mutations in CHMP2B were first identified in a large Danish pedigree with autosomal dominant FTD, and have also been found in several individuals from Belgium, France, the United States, and Türkiye. In the Chinese population, cases of CHMP2B variant-associated FTD have never been reported.

Methods: The spectrum of clinical symptoms and the genetic analysis of the presented patient were identified and investigated. Besides this case, we assessed previously reported cases with CHMP2B gene mutations.

Results: This study presents a Chinese patient harboring a novel heterozygous A-to-T variant (NM_014043:c.532-2A>T) in CHMP2B with a phenotype compatible with FTD. Although previous reports suggested cases of CHMP2B variant-associated FTD initially presented with personality changes and stereotypical movements at the age of 50, this case was characterized by psychosis involving delusion of persecution, auditory hallucination, and suspiciousness at the earlier onset age of 44. Minigene splicing assay revealed that the splice-site variant could result in the retention of intron 5.

Conclusion: This is the first case of CHMP2B variant-associated FTD reported in the Chinese population. The novel c.532-2A>T variant in the acceptor splice site of exon 6 retaining intron 5 was predicted to cause truncated protein and protein conformation changes. This discovery may expand the genetic and phenotypic spectrum of CHMP2B variant-associated FTD.

Keywords: CHMP2B; exon 6; frontotemporal dementia (FTD); novel variant; splice.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no conflict of interest.

Figures

FIGURE 1
FIGURE 1
Imaging and genetic results of the family. (a) Pedigree of the FTD family. (b) Brain MRI revealed frontotemporal atrophy, enlargement of the anterior horn of the lateral ventricle, and mild atrophy of the bilateral hippocampi. (c) The result of Sanger sequencing of the patient. A heterozygous mutation (NM_014043:c.532‐2A>T) of the CHMP2B gene was identified.
FIGURE 2
FIGURE 2
The results of the Minigene splicing assay. (a) CHMP2B transcript sequencing: the complete 201‐bp sequence of intron 5 was retained in the mutant mRNA, and the prolonged mRNA is represented as follows: NM_014043:c.532‐1_532‐201ins. (b) Gel electrophoresis of the CHMP2B mutant type showed one 1054 bp band, whereas the CHMP2B wild‐type showed one 853 bp band. (c) Schematic diagram of splicing: the effect of variation on mRNA splicing resulted in retaining the intact sequence of intron 5 in the mRNA.
FIGURE 3
FIGURE 3
Predicted molecular modeling. (a and b) AlphaFold software was used to develop a suitable model to simulate the effect of the mutation region; the 3D protein modeling predicted that compared with wild type (a), the mutation would result in a truncated protein with a complete absence of the translated portion of exon 6 protein (b). (c) The portion of the mutant deletion contains three α‐helixes. (d) The mutant CHMP2B102 methionine position shows the change of the hydrogen bonds, which produced hydrogen bonds interaction with ALA99, whereas the wild‐type MET102 produced hydrogen bonds' interaction with MET96 and ALA106. (e) The mutant CHMP2B152 glycine position shows the change in hydrogen bonds, which interacts with ASP148, ASP151, ASP155, and GLU156, whereas the wild‐type GLY152 produced hydrogen bonds' interactions with ASP155and GLU156.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

References

    1. Alqabandi, M. , de Franceschi, N. , Maity, S. , Miguet, N. , Bally, M. , Roos, W. H. , Weissenhorn, W. , Bassereau, P. , & Mangenot, S. (2021). The ESCRT‐III isoforms CHMP2A and CHMP2B display different effects on membranes upon polymerization. BMC Biology, 19(1), 66. 10.1186/s12915-021-00983-9 - DOI - PMC - PubMed
    1. Artan, S. , Erzurumluoglu Gokalp, E. , Samanci, B. , Ozbabalik Adapinar, D. , Bas, H. , Tepgec, F. , Qomi Ekenel, E. , Cilingir, O. , Bilgic, B. , Gurvit, H. , Hanagasi, H. A. , Kocagil, S. , Durak Aras, B. , Uyguner, O. , & Emre, M. (2021). Frequency of frontotemporal dementia‐related gene variants in Turkey. Neurobiology of Aging, 106, 332–332.e11. 10.1016/j.neurobiolaging.2021.05.007 - DOI - PubMed
    1. Cannon, A. , Baker, M. , Boeve, B. , Josephs, K. , Knopman, D. , Petersen, R. , Parisi, J. , Dickison, D. , Adamson, J. , Snowden, J. , Neary, D. , Mann, D. , Hutton, M. , & Pickering‐Brown, S. M. (2006). CHMP2B mutations are not a common cause of frontotemporal lobar degeneration. Neuroscience Letters, 398(1–2), 83–84. 10.1016/j.neulet.2005.12.056 - DOI - PubMed
    1. Ferrari, R. , Kapogiannis, D. , Huey, E. D. , Grafman, J. , Hardy, J. , & Momeni, P. (2010). Novel missense mutation in charged multivesicular body protein 2B in a patient with frontotemporal dementia. Alzheimer Disease and Associated Disorders, 24(4), 397–401. 10.1097/WAD.0b013e3181df20c7 - DOI - PMC - PubMed
    1. Ghanim, M. , Guillot‐Noel, L. , Pasquier, F. , Jornea, L. , Deramecourt, V. , Dubois, B. , Le Ber, I. , & Brice, A. (2010). CHMP2B mutations are rare in French families with frontotemporal lobar degeneration. Journal of Neurology, 257(12), 2032–2036. 10.1007/s00415-010-5655-8 - DOI - PubMed

MeSH terms

Substances

LinkOut - more resources