title: Closing the tau loop: the missing tau mutation.
abstract: Frontotemporal lobar degeneration comprises a group of disorders characterized by behavioural, executive, language impairment and sometimes features of parkinsonism and motor neuron disease. In 1994 we described an Irish-American family with frontotemporal dementia linked to chromosome 17 associated with extensive tau pathology. We named this disinhibition-dementia-parkinsonism-amyotrophy complex. We subsequently identified mutations in the MAPT gene. Eleven MAPT gene splice site stem loop mutations were identified over time except for 5' splice site of exon 10. We recently identified another Irish family with autosomal dominant early amnesia and behavioural change or parkinsonism associated with the 'missing' +15 mutation at the intronic boundary of exon 10. We performed a clinical, neuropsychological and neuroimaging study on the proband and four siblings, including two affected siblings. We sequenced MAPT and performed segregation analysis. We looked for a biological effect of the tau variant by performing real-time polymerase chain reaction analysis of RNA extracted from human embryonic kidney cells transfected with exon trapping constructs. We found a c.915+15A>C exon 10/intron 10 stem loop mutation in all affected subjects but not in the unaffected. The c.915+15A>C variant caused a shift in tau splicing pattern to a predominantly exon 10+ pattern presumably resulting in predominant 4 repeat tau and little 3 repeat tau. This strongly suggests that the c.915+15A>C variant is a mutation and that it causes frontotemporal dementia linked to chromosome 17 in this pedigree by shifting tau transcription and translation to +4 repeat tau. Tau (MAPT) screening should be considered in families where amnesia or atypical parkinsonism coexists with behavioural disturbance early in the disease process. We describe the final missing stem loop tau mutation predicted 15 years ago. Mutations have now been identified at all predicted sites within the 'stem' when the stem-loop model was first proposed and no mutations have been found within the 'loop' region as expected. Therefore we 'close the tau loop' having 'opened the loop' 21 years ago.
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Allan
authors: A
authors: McCarthy
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Roisin
authors: R
authors: Lonergan
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Diana A
authors: DA
authors: Olszewska
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Sean
authors: S
authors: O'Dowd
authors: 2 Department of Clinical Neuroscience, Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge, CB2 0PY, UK.
authors: Gemma
authors: G
authors: Cummins
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Brian
authors: B
authors: Magennis
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Emer M
authors: EM
authors: Fallon
authors: 3 Department of Psychology, Beaumont Hospital, Beaumont Rd, Dublin 9, Ireland, Department of Psychology, Royal College of Surgeons in Ireland.
authors: Niall
authors: N
authors: Pender
authors: 4 Departments of Psychiatry and Neurology, College of Physicians and Surgeons, University Medical Centre, 630 West 168th Street, New York, NY 10032, USA.
authors: Edward D
authors: ED
authors: Huey
authors: 5 Cognitive Neuroscience Section, Department of Neurology, Columbia University Medical Centre, 630 West 168th Street, New York, NY 10032, USA.
authors: Stephanie
authors: S
authors: Cosentino
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland.
authors: Killian
authors: K
authors: O'Rourke
authors: 6 Department of Psychiatry, Mater Misericordiae University Hospital, 63 Eccles Street, Dublin 7, Ireland.
authors: Brendan D
authors: BD
authors: Kelly
authors: 7 Department of Radiology, Mater Misericordiae University Hospital, North Circular Road, Dublin 7, Ireland.
authors: Martin
authors: M
authors: O'Connell
authors: 8 Medical Genetics Service, Cambridge University Hospital NHS Foundation Trust, Addenbrooke's Treatment Centre, Hills Road, Cambridge, CB2 0QQ, UK.
authors: Isabelle
authors: I
authors: Delon
authors: 9 Department of Neuropathology, Beaumont Hospital, Beaumont Road, Dublin, Ireland.
authors: Michael
authors: M
authors: Farrell
authors: 10 Department of Clinical Neurosciences, Clifford Allbutt Building, University of Cambridge, Cambridge, CB2 0AH, UK.
authors: Maria Grazia
authors: MG
authors: Spillantini
authors: 11 The Neurological Institute, Columbia University, 710 West 168th Street, New York, NY 10032-3784, USA.
authors: Lewis P
authors: LP
authors: Rowland
authors: 11 The Neurological Institute, Columbia University, 710 West 168th Street, New York, NY 10032-3784, USA.
authors: Stanley
authors: S
authors: Fahn
authors: 12 Eli Lilly, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
authors: Peter
authors: P
authors: Craig
authors: 12 Eli Lilly, Erl Wood Manor, Windlesham, Surrey, GU20 6PH, UK.
authors: Michael
authors: M
authors: Hutton
authors: 1 The Dublin Neurological Institute at the Mater Misericordiae University Hospital, 57 Eccles Street, Dublin 7, Ireland tlynch@dni.ie.
authors: Tim
authors: T
authors: Lynch
mesh_terms: D001921:Brain / Q000473:pathology*; D005192:Family Health; D019788:Fluorodeoxyglucose F18; D057180:Frontotemporal Dementia / Q000000981:diagnostic imaging / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D049268:Positron-Emission Tomography; D016875:tau Proteins / Q000235:genetics*
chemical_list: D016875:tau Proteins; D019788:Fluorodeoxyglucose F18
keywords: FTDP-17; MAPT; dementia; frontotemporal; stem loop