Slowly progressive behavioral frontotemporal dementia syndrome in a family co-segregating the C9orf72 expansion and a Synaptophysin mutation.
C9orf72
SYP
behavioral frontotemporal dementia
familial dementia
synaptophysin
whole-exome sequencing
Journal
Alzheimer's & dementia : the journal of the Alzheimer's Association
ISSN: 1552-5279
Titre abrégé: Alzheimers Dement
Pays: United States
ID NLM: 101231978
Informations de publication
Date de publication:
03 2022
03 2022
Historique:
revised:
08
06
2021
received:
16
10
2020
accepted:
08
06
2021
pubmed:
27
7
2021
medline:
26
4
2022
entrez:
26
7
2021
Statut:
ppublish
Résumé
Synaptophysin, already related to X-linked intellectual disability, is expressed mainly in the central nervous system. Studies in humans indicate that the downregulation of synaptophysin could be involved in the development of dementia. Our study presents the first familial case of behavioral variant frontotemporal dementia associated with the co-occurrence of the repeat expansion in C9orf72 and a pathogenic variant in the SYP gene. Exome sequencing and repeat-primed PCR for C9orf72 were performed for two siblings with clinical and imaging findings suggestive of slowly progressive behavioral frontotemporal dementia. We found that both siblings have the hexanucleotide expansion in C9orf72 and a null variant in the SYP gene. The most affected sibling presents the putative variant in a hemizygous state. With milder symptoms, his sister has the same pathogenic variant in heterozygosis, compatible with X-linked inheritance. Our results strengthened previous suggestive evidence that the phenotypes associated with C9orf72 repeat expansion are variable and probably influenced by additional genetic modifiers. We hypothesized that the pathogenic variant in the SYP gene might have modified the typical phenotype associated with the C9orf72 mutation.
Substances chimiques
C9orf72 Protein
0
C9orf72 protein, human
0
Proteins
0
Synaptophysin
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
523-528Informations de copyright
© 2021 the Alzheimer's Association.
Références
Rascovsky K, Hodges JR, Knopman D, et al. Sensitivity of revised diagnostic criteria for the behavioural variant of frontotemporal dementia. Brain. 2011; 134(Pt 9):2456-2477.
Ranganathan R, Haque S, Coley K, Shepheard S, Cooper-Knock J, Kirby J. Multifaceted genes in amyotrophic lateral sclerosis-frontotemporal dementia. Front Neurosci. 2020;14:684.
Cooper-Knock J, Shaw PJ, Kirby J. The widening spectrum of C9ORF72-related disease; genotype/phenotype correlations and potential modifiers of clinical phenotype. Acta Neuropathol. 2014;127(3):333-345.
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17(5):405-424.
Rocha CS, Secolin R, Rodrigues MR, Carvalho BS, Lopes-Cendes I. The Brazilian Initiative on Precision Medicine (BIPMed): fostering genomic data-sharing of underrepresented populations. NPJ Genom Med. 2020;5:42.
Wan J, Qian SB. TISdb: a database for alternative translation initiation in mammalian cells. Nucleic Acids Res. 2014;42(Database issue):D845-50.
Gordon SL, Cousin MA. X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval. J Neurosci. 2013;33(34):13695-3700.
Akimoto C, Volk AE, van Blitterswijk M, et al. A blinded international study on the reliability of genetic testing for GGGGCC-repeat expansions in C9orf72 reveals marked differences in results among 14 laboratories. J Med Genet. 2014;51(6):419-424.
Goldman JS, Van Deerlin VM. Alzheimer's disease and frontotemporal dementia: The current state of genetics and genetic testing since the advent of next-generation sequencing. Mol Diagn Ther. 2018;22(5):505-513.
van Blitterswijk M, van Es MA, Hennekam EA, et al. Evidence for an oligogenic basis of amyotrophic lateral sclerosis. Hum Mol Genet. 2012;21(17):3776-3784.
van der Zee J, Gijselinck I, Van Mossevelde S, et al. TBK1 mutation spectrum in an extended European patient cohort with frontotemporal dementia and amyotrophic lateral sclerosis. Hum Mutat. 2017;38(3):297-309.
Gordon SL, Cousin MA. X-linked intellectual disability-associated mutations in synaptophysin disrupt synaptobrevin II retrieval. J Neurosci. 2013;33(34):13695-13700.
Tarpey PS, Smith R, Pleasance E, et al. A systematic, large-scale resequencing screen of X-chromosome coding exons in mental retardation. Nat Genet. 2009;41(5):535-543.
Shen YC, Tsai HM, Ruan JW, Liao YC, Chen SF, Chen CH. Genetic and functional analyses of the gene encoding synaptophysin in schizophrenia. Schizophr Res. 2012;137(1-3):14-19.
Chi LM, Wang X, Nan GX. In silico analyses for molecular genetic mechanism and candidate genes in patients with Alzheimer's disease. Acta Neurol Belg. 2016;116(4):543-547.
Zhang W, Wang GM, Wang PJ, Zhang Q, Sha SH. Effects of neural stem cells on synaptic proteins and memory in a mouse model of Alzheimer's disease. J Neurosci Res. 2014;92(2):185-194.
Liu L, Chen Y, Li H, et al. Association between SYP with attention-deficit/hyperactivity disorder in Chinese Han subjects: differences among subtypes and genders. Psychiatry Res. 2013;210(1):308-314.
Gudi V, Gai L, Herder V, et al. Synaptophysin is a reliable marker for axonal damage. J Neuropathol Exp Neurol. 2017;76(2):109-125.
Kwon SE, Chapman ER. Synaptophysin regulates the kinetics of synaptic vesicle endocytosis in central neurons. Neuron. 2011;70(5):847-854.