title: A novel mutation P112H in the TARDBP gene associated with frontotemporal lobar degeneration without motor neuron disease and abundant neuritic amyloid plaques.
abstract: BACKGROUND
  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.
authors: Fermin
authors: F
authors: Moreno
authors: Gil D
authors: GD
authors: Rabinovici
authors: Anna
authors: A
authors: Karydas
authors: Zachary
authors: Z
authors: Miller
authors: Sandy Chan
authors: SC
authors: Hsu
authors: Andrea
authors: A
authors: Legati
authors: Jamie
authors: J
authors: Fong
authors: Daniel
authors: D
authors: Schonhaut
authors: Hermann
authors: H
authors: Esselmann
authors: Christa
authors: C
authors: Watson
authors: Melanie L
authors: ML
authors: Stephens
authors: Joel
authors: J
authors: Kramer
authors: Jens
authors: J
authors: Wiltfang
authors: William W
authors: WW
authors: Seeley
authors: Bruce L
authors: BL
authors: Miller
authors: Giovanni
authors: G
authors: Coppola
authors: Lea Tenenholz
authors: LT
authors: Grinberg
mesh_terms: D000368:Aged; D001921:Brain / Q000473:pathology*; D004268:DNA-Binding Proteins / Q000235:genetics*; D003704:Dementia / Q000235:genetics / Q000473:pathology; D005260:Female; D057174:Frontotemporal Lobar Degeneration / Q000235:genetics* / Q000473:pathology*; D006801:Humans; D002479:Inclusion Bodies / Q000473:pathology; D008297:Male; D008875:Middle Aged; D016472:Motor Neuron Disease / Q000235:genetics / Q000473:pathology; D009154:Mutation; D020734:Parkinsonian Disorders / Q000235:genetics / Q000473:pathology; D010375:Pedigree; D058225:Plaque, Amyloid / Q000473:pathology*; D035781:Siblings
chemical_list: D004268:DNA-Binding Proteins; C000598624:TARDBP protein, human