The new mutation, E46K, of alpha-synuclein causes Parkinson and Lewy body dementia.
Familial parkinsonism and dementia with cortical and subcortical Lewy bodies is uncommon, and no genetic defect has been reported in the previously described sibships. We present a Spanish family with autosomal dominant parkinsonism, dementia, and visual hallucinations of variable severity. The postmortem examination showed atrophy of the substantia nigra, lack of Alzheimer pathology, and numerous Lewy bodies which were immunoreactive to alpha-synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the alpha-synuclein gene showed a novel, nonconservative E46K mutation in heterozygosis. The E46K mutation was present in all affected family members and in three young asymptomatic subjects, but it was absent in healthy and pathological controls. The novel mutation, that substitutes a dicarboxylic amino acid, glutamic acid, with a basic amino acid such as lysine in a much conserved area of the protein, is likely to produce severe disturbance of protein function. Our data show that, in addition to the previously described hereditary alpha-synucleinopathies, dementia with Lewy bodies is related to mutation of alpha-synuclein.
Zarranz
Juan J
JJ
Department of Neurology, de Cruces Hospital, Departament of Neuroscience, University del País Vasco, Baracaldo, Vizcaya, Spain. jjzarranz@hcru.osakidetza.net
Alegre
Javier
J
Gómez-Esteban
Juan C
JC
Lezcano
Elena
E
Ros
Raquel
R
Ampuero
Israel
I
Vidal
Lídice
L
Hoenicka
Janet
J
Rodriguez
Olga
O
Atarés
Begoña
B
Llorens
Verónica
V
Gomez Tortosa
Estrella
E
del Ser
Teodoro
T
Muñoz
David G
DG
de Yebenes
Justo G
JG
D000368:Aged; D000595:Amino Acid Sequence; D001483:Base Sequence; D001921:Brain / Q000473:pathology*; D004252:DNA Mutational Analysis; D017931:DNA Primers; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D016631:Lewy Bodies / Q000473:pathology; D020961:Lewy Body Disease / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009410:Nerve Degeneration / Q000473:pathology; D009419:Nerve Tissue Proteins / Q000235:genetics*; D010300:Parkinson Disease / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D016133:Polymerase Chain Reaction; D017385:Sequence Homology; D051843:Synucleins; D015899:Tomography, Emission-Computed, Single-Photon; D051844:alpha-Synuclein
D017931:DNA Primers; D009419:Nerve Tissue Proteins; C497604:SNCA protein, human; D051843:Synucleins; D051844:alpha-Synuclein