A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.

Publisher: BioMed Central Country of Publication: England NLM ID: 101610673 Publication Model: Electronic Cited Medium: Internet ISSN: 2051-5960 (Electronic) Linking ISSN: 20515960 NLM ISO Abbreviation: Acta Neuropathol Commun Subsets: MEDLINE

Original Publication: London : BioMed Central, [2013]-

Brain/*pathology ; DNA-Binding Proteins/*genetics ; Frontotemporal Lobar Degeneration/*genetics ; Frontotemporal Lobar Degeneration/*pathology ; Plaque, Amyloid/*pathology; Dementia/genetics ; Dementia/pathology ; Inclusion Bodies/pathology ; Motor Neuron Disease/genetics ; Motor Neuron Disease/pathology ; Parkinsonian Disorders/genetics ; Parkinsonian Disorders/pathology ; Aged ; Female ; Humans ; Male ; Middle Aged ; Mutation ; Pedigree ; Siblings

Introduction: Although TDP-43 is the main constituent of the ubiquitinated cytoplasmic inclusions in the most common forms of frontotemporal lobar degeneration, TARDBP mutations are not a common cause of familial frontotemporal dementia, especially in the absence of motor neuron disease.
Results: We describe a pedigree presenting with a complex autosomal dominant disease, with a heterogeneous clinical phenotype, comprising unspecified dementia, parkinsonism, frontotemporal dementia and motor neuron disease. Genetic analyses identified a novel P112H TARDBP double variation located in exon 3 coding for the first RNA recognition motif of the protein (RRM1). This double mutation is probably pathogenic based on neuropathological findings, in silico prediction analysis and exome sequencing. The two autopsied siblings described here presented with frontotemporal dementia involving multiple cognitive domains and behavior but lacking symptoms of motor neuron disease throughout the disease course. The siblings presented with strikingly similar, although atypical, neuropathological features, including an unclassifiable TDP-43 inclusion pattern, a high burden of tau-negative β-amyloid neuritic plaques with an AD-like biochemical profile, and an unclassifiable 4-repeat tauopathy. The co-occurrence of multiple protein inclusions points to a pathogenic mechanism that facilitates misfolded protein interaction and aggregation or a loss of TDP-43 function that somehow impairs protein clearance.
Conclusions: TARDBP mutation screening should be considered in familial frontotemporal dementia cases, even without signs or symptoms of motor neuron disease, especially when other more frequent causes of genetic frontotemporal dementia (i.e. GRN, C9ORF72, MAPT) have been excluded and when family history is complex and includes parkinsonism, motor neuron disease and frontotemporal dementia. Further investigations in this family may provide insight into the physiological functions of TARDBP.

J Biol Chem. 2001 Sep 28;276(39):36337-43. (PMID: 11470789)
Neurology. 2002 Jun 25;58(12):1791-800. (PMID: 12084879)
J Neurochem. 2003 Jun;85(6):1581-91. (PMID: 12787077)
Nucleic Acids Res. 2003 Jul 1;31(13):3812-4. (PMID: 12824425)
J Neurol Neurosurg Psychiatry. 2003 Nov;74(11):1574-6. (PMID: 14617722)
Ann Neurol. 2004 Sep;56(3):399-406. (PMID: 15349867)
J Psychiatr Res. 1975 Nov;12(3):189-98. (PMID: 1202204)
Acta Neuropathol. 1991;82(4):239-59. (PMID: 1759558)
Neurology. 2005 Aug 23;65(4):586-90. (PMID: 16116120)
Clin Chem. 2005 Sep;51(9):1650-60. (PMID: 16020497)
Neurology. 2005 Dec 13;65(11):1817-9. (PMID: 16344531)
Science. 2006 Oct 6;314(5796):130-3. (PMID: 17023659)
Neurosci Lett. 2007 May 23;419(1):1-4. (PMID: 17434264)
Acta Neuropathol. 2007 Jul;114(1):5-22. (PMID: 17579875)
Nucleic Acids Res. 2007;35(11):3823-35. (PMID: 17526529)
Science. 2008 Mar 21;319(5870):1668-72. (PMID: 18309045)
Lancet Neurol. 2008 May;7(5):409-16. (PMID: 18396105)
Nat Genet. 2008 May;40(5):572-4. (PMID: 18372902)
Ann Neurol. 2008 Apr;63(4):535-8. (PMID: 18288693)
Ann Neurol. 2008 Apr;63(4):538-42. (PMID: 18438952)
Eur J Neurol. 2008 Aug;15(8):772-80. (PMID: 18684309)
Arch Neurol. 2008 Sep;65(9):1185-9. (PMID: 18779421)
PLoS Genet. 2008;4(9):e1000193. (PMID: 18802454)
J Cell Sci. 2008 Nov 15;121(Pt 22):3778-85. (PMID: 18957508)
Neurobiol Aging. 2009 Jan;30(1):157-9. (PMID: 17614162)
J Med Genet. 2009 Feb;46(2):112-4. (PMID: 18931000)
Ann Neurol. 2009 Apr;65(4):470-3. (PMID: 19350673)
Neurobiol Aging. 2009 Aug;30(8):1329-31. (PMID: 18068872)
Mov Disord. 2009 Sep 15;24(12):1843-7. (PMID: 19609911)
Dement Geriatr Cogn Disord. 2009;28(3):239-43. (PMID: 19786775)
Acta Neuropathol. 2009 Nov;118(5):633-45. (PMID: 19618195)
Hum Mutat. 2009 Nov;30(11):E974-83. (PMID: 19655382)
Nat Methods. 2010 Apr;7(4):248-9. (PMID: 20354512)
Neurogenetics. 2010 May;11(2):217-25. (PMID: 19760257)
Eur Neurol. 2010;63(5):291-4. (PMID: 20413973)
Arch Neurol. 2010 Aug;67(8):1002-9. (PMID: 20697052)
Lancet Neurol. 2010 Oct;9(10):995-1007. (PMID: 20864052)
Rejuvenation Res. 2010 Oct;13(5):509-17. (PMID: 20645878)
Brain Res. 2011 Apr 22;1386:191-9. (PMID: 21376022)
Arch Neurol. 2011 May;68(5):594-8. (PMID: 21220647)
Acta Neuropathol. 2011 Jul;122(1):111-3. (PMID: 21644037)
Neurogenetics. 2011 Aug;12(3):203-9. (PMID: 21667065)
Neurobiol Aging. 2011 Dec;32(12):2327.e1-5. (PMID: 21803454)
Neuron. 2011 Oct 20;72(2):245-56. (PMID: 21944778)
Curr Opin Neurol. 2011 Dec;24(6):542-9. (PMID: 21986680)
Acta Neuropathol. 2012 Jan;123(1):1-11. (PMID: 22101365)
Neurobiol Aging. 2012 Aug;33(8):1846.e1-4. (PMID: 22398199)
Parkinsonism Relat Disord. 2013 Mar;19(3):312-5. (PMID: 23231971)
Neurogenetics. 2013 May;14(2):161-6. (PMID: 23546887)
Neuropathol Appl Neurobiol. 2014 Feb;40(2):225-30. (PMID: 23692129)
Neurobiol Aging. 2014 May;35(5):1212.e1-5. (PMID: 24300238)

P50 AG023501 United States AG NIA NIH HHS; U24 AG021886 United States AG NIA NIH HHS; P50AG023501 United States AG NIA NIH HHS; U24AG21886 United States AG NIA NIH HHS; P01 AG019724 United States AG NIA NIH HHS; P01AG019724 United States AG NIA NIH HHS

0 (DNA-Binding Proteins)
0 (TARDBP protein, human)

Date Created: 20150409 Date Completed: 20160113 Latest Revision: 20201109

20260130

PMC4382926

10.1186/s40478-015-0190-6

25853458