MAPT p.V363I mutation: A rare cause of corticobasal degeneration

Sarah Ahmed¹, Monica Diez Fairen¹, Marya S Sabir¹, Pau Pastor¹, Jinhui Ding¹, Lourdes Ispierto¹, Ankur Butala¹, Christopher M Morris¹, Claudia Schulte¹, Thomas Gasser¹, Edwin Jabbari¹, Olga Pletnikova¹, Huw R Morris¹, Juan Troncoso¹, Ellen Gelpi¹, Alexander Pantelyat¹, Sonja W Scholz¹

Affiliations

Affiliation

¹ Neurodegenerative Disease Research Unit (S.A., M.S.S., S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Movement Disorders and Memory Unit (M.D.F., P.P.), Department of Neurology, University Hospital Mutua de Terrassa, and Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Barcelona, Spain; Laboratory of Neurogenetics (J.D.), National Institutes on Aging, National Institutes of Health, Bethesda, MD; Neurology Service (L.I.), Hospital Universitari Germans Trias, Pujol, Badalona, Spain; Department of Neurology (A.B., A.P., S.W.S.), Johns Hopkins University Medical Center, Baltimore, MD; Newcastle Institute for Ageing (C.M.M.), Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Neurodegenerative Diseases (C.S., T.G.), Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, and German Center for Neurodegenerative Diseases, Germany; Department of Molecular and Clinical Neuroscience (E.J., H.R.M.), Institute of Neurology, University College London, United Kingdom; Department of Pathology (Neuropathology) (O.P., J.T.), Johns Hopkins University Medical Center, Baltimore, MD; Department of Clinical Neurosciences (H.R.M.), Royal Free Campus UCL, Institute of Neurology, London, United Kingdom; Neurological Tissue Bank (E.G.), University of Barcelona-Hospital Clinic, IDIBAPS, Barcelona, Spain; and Institute of Neurology (E.G.), Medical University of Vienna, Austria.

PMID: 31404212
PMCID: PMC6659135
DOI: 10.1212/NXG.0000000000000347

MAPT p.V363I mutation: A rare cause of corticobasal degeneration

Sarah Ahmed et al. Neurol Genet. 2019.

. 2019 Jun 25;5(4):e347.

doi: 10.1212/NXG.0000000000000347. eCollection 2019 Aug.

Authors

Affiliation

¹ Neurodegenerative Disease Research Unit (S.A., M.S.S., S.W.S.), National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD; Movement Disorders and Memory Unit (M.D.F., P.P.), Department of Neurology, University Hospital Mutua de Terrassa, and Fundació per la Recerca Biomèdica i Social Mútua Terrassa, Barcelona, Spain; Laboratory of Neurogenetics (J.D.), National Institutes on Aging, National Institutes of Health, Bethesda, MD; Neurology Service (L.I.), Hospital Universitari Germans Trias, Pujol, Badalona, Spain; Department of Neurology (A.B., A.P., S.W.S.), Johns Hopkins University Medical Center, Baltimore, MD; Newcastle Institute for Ageing (C.M.M.), Campus for Ageing and Vitality, Newcastle University, Newcastle upon Tyne, United Kingdom; Department of Neurodegenerative Diseases (C.S., T.G.), Center of Neurology, Hertie-Institute for Clinical Brain Research, University of Tuebingen, and German Center for Neurodegenerative Diseases, Germany; Department of Molecular and Clinical Neuroscience (E.J., H.R.M.), Institute of Neurology, University College London, United Kingdom; Department of Pathology (Neuropathology) (O.P., J.T.), Johns Hopkins University Medical Center, Baltimore, MD; Department of Clinical Neurosciences (H.R.M.), Royal Free Campus UCL, Institute of Neurology, London, United Kingdom; Neurological Tissue Bank (E.G.), University of Barcelona-Hospital Clinic, IDIBAPS, Barcelona, Spain; and Institute of Neurology (E.G.), Medical University of Vienna, Austria.

PMID: 31404212
PMCID: PMC6659135
DOI: 10.1212/NXG.0000000000000347

Abstract

Objective: Patients with corticobasal syndrome (CBS) present with heterogeneous clinical features, including asymmetric parkinsonism, dyspraxia, aphasia, and cognitive impairment; to better understand the genetic etiology of this rare disease, we undertook a genetic analysis of microtubule-associated protein tau (MAPT).

Methods: We performed a genetic evaluation of MAPT mutations in 826 neurologically healthy controls and 173 cases with CBS using the Illumina NeuroChip genotyping array.

Results: We identified 2 patients with CBS heterozygous for a rare mutation in MAPT (p.V363I) that is located in the highly conserved microtubule-binding domain. One patient was pathologically confirmed and demonstrated extensive 4-repeat-tau-positive thread pathology, achromatic neurons, and astrocytic plaques consistent with corticobasal degeneration (CBD).

Conclusions: We report 2 CBS cases carrying the rare p.V363I MAPT mutation, one of which was pathologically confirmed as CBD. Our findings support the notion that this rare coding change is pathogenic.

PubMed Disclaimer

Figures

**Figure 1. This schematic representation illustrates the location of the *MAPT* p.V363I mutation**
A Cartesian genotype plot and electropherograms of this mutation are shown for both CBS cases compared with a control (A). The mutation is localized within the highly conserved microtubule-binding domain (B). (C) Position of the p.V363I mutation (arrow heads) within the microtubule-binding domain (highlighted in purple) relative to the 3-dimensional reconstruction of the tau protofibril. *MAPT* = microtubule-associated protein tau.

**Figure 2. These images showcase the pertinent neuropathologic findings of case 2**
Hematoxylin and eosin staining shows superficial spongiosis in the postcentral region (A), a large achromatic or ballooned cell (highlighted by asterisk in B), and prominent nigral degeneration with severe neuronal loss and abundant extracellular neuromelanin pigment (C). (D–I) Abnormal pTau (AT8) and 4-repeat-tau-positive protein deposition on immunohistochemistry. Notable abnormal histopathologic findings included astrocytic plaques (D), frequent pretangles with some focal cytoplasmic condensations (E), tangles, pretangles, and abundant threads in the substantia nigra (F), very abundant threads (arrow heads) and coiled bodies (arrow) in the white matter (G and H), and abundant threads and pretangles in the striatum (I), overall consistent with the neuropathologic findings observed in corticobasal degeneration. Magnification scale bars are indicated in the bottom right corner of each panel.

See this image and copyright information in PMC

References

1. Kouri N, Murray ME, Hassan A, et al. . Neuropathological features of corticobasal degeneration presenting as corticobasal syndrome or Richardson syndrome. Brain 2011;134:3264–3275. - PMC - PubMed
1. Poorkaj P, Bird TD, Wijsman E, et al. . Tau is a candidate gene for chromosome 17 frontotemporal dementia. Ann Neurol 1998;43:815–825. - PubMed
1. Hutton M, Lendon CL, Rizzu P, et al. . Association of missense and 5'-splice-site mutations in tau with the inherited dementia FTDP-17. Nature 1998;393:702–705. - PubMed
1. Spillantini MG, Murrell JR, Goedert M, Farlow MR, Klug A, Ghetti B. Mutation in the tau gene in familial multiple system tauopathy with presenile dementia. Proc Natl Acad Sci U S A 1998;95:7737–7741. - PMC - PubMed
1. Pickering-Brown SM, Rollinson S, Du Plessis D, et al. . Frequency and clinical characteristics of progranulin mutation carriers in the Manchester frontotemporal lobar degeneration cohort: comparison with patients with MAPT and no known mutations. Brain 2008;131:721–731. - PubMed

Grants and funding

LinkOut - more resources

Full Text Sources

Save citation to file

Email citation

Add to Collections

Add to My Bibliography

Your saved search

Create a file for external citation management software

Your RSS Feed

MAPT p.V363I mutation: A rare cause of corticobasal degeneration

Affiliation

MAPT p.V363I mutation: A rare cause of corticobasal degeneration

Authors

Affiliation

Abstract

Figures

References

Grants and funding

LinkOut - more resources

Full Text Sources