A clinical, molecular genetics and pathological study of a FTDP-17 family with a heterozygous splicing variant c.823-10G>T at the intron 9/exon 10 of the MAPT gene

• Published in: Neurobiology of aging 2021-10, Vol.106, p.343.e1-343.e8
• Main Authors: Olszewska, Diana A., Fearon, Conor, McGuigan, Christopher, McVeigh, Terri P, Houlden, Henry, Polke, James M, Lawlor, Brian, Coen, Robert, Hutchinson, Michael, Hutton, Michael, Beausang, Alan, Delon, Isabelle, Brett, Francesca, Sevastou, Ioanna, Seto-Salvia, Nuria, de Silva, Rohan, Lynch, Tim
• Format: Article
• Language: English
• Subjects: Aged; Brain - diagnostic imaging; c.823-10G>T; Chromosomes, Human, Pair 17 - genetics; Exons - genetics; Female; Frontotemporal dementia; Frontotemporal Dementia - diagnostic imaging; Frontotemporal Dementia - genetics; Frontotemporal Dementia - pathology; Genetic Association Studies - methods; Genetics; Heterozygote; Humans; Intron 9/exon 10 mutation; Introns - genetics; Magnetic Resonance Imaging; Male; Middle Aged; Motor Neuron Disease - genetics; Neuroimaging; Neuropathology; Parkinsonian Disorders - diagnostic imaging; Parkinsonian Disorders - genetics; Parkinsonian Disorders - pathology; Point Mutation - genetics; tau Proteins - genetics; Tauopathies - genetics
• ISSN: 0197-4580; 1558-1497; 1558-1497
• DOI: 10.1016/j.neurobiolaging.2021.05.010

•c.823-10G>T Microtubule associated tau (MAPT) gene variant was reported in one family with frontotemporal dementia.•No pathological data was available confirming the disease.•This is the first description of the pathology confirming that the variant is disease causing.•This is the first description of the MND associated with c.823-10G>T MAPT variant. We report the first clinical-radiological-genetic-molecular-pathological study of a kindred with c.823-10G>T MAPT intronic variant (rs63749974) associated with frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17). We describe the clinical spectrum within this family and emphasize the association between MAPT gene variants and motor neuron disease. This report of a second family with FTDP-17 associated with c.823-10G>T MAPT variant strongly supports pathogenicity of the variant and confirms it is a 4-repeat (4R) tauopathy. This intronic point mutation, probably strengthens the polypyrimidine tract and alters the splicing of exon 10 (10 nucleotides into intron 9) close to the 3’ splice site.