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The new mutation, E46K, of α‐synuclein causes parkinson and Lewy body dementia
Author(s) -
Zarranz Juan J.,
Alegre Javier,
GómezEsteban Juan C.,
Lezcano Elena,
Ros Raquel,
Ampuero Israel,
Vidal Lídice,
Hoenicka Janet,
Rodriguez Olga,
Atarés Begoña,
Llorens Verónica,
Tortosa Estrella Gomez,
del Ser Teodoro,
Muñoz David G.,
de Yebenes Justo G.
Publication year - 2004
Publication title -
annals of neurology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.764
H-Index - 296
eISSN - 1531-8249
pISSN - 0364-5134
DOI - 10.1002/ana.10795
Subject(s) - dementia with lewy bodies , parkinsonism , synucleinopathies , lewy body , alpha synuclein , dementia , mutation , synuclein , atrophy , biology , pathology , substantia nigra , parkinson's disease , neuroscience , genetics , medicine , gene , disease
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 α‐synuclein and ubiquitin in cortical and subcortical areas. Sequencing of the α‐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 α‐synucleinopathies, dementia with Lewy bodies is related to mutation of α‐synuclein.