Clinical genetic analysis of Parkinson's disease in the contursi kindred

Golbe, Lawrence I.; Lazzarini, Alice; Duvoisin, Roger C.; Iorio, Giuseppe Di; Sanges, G.; Bonavita, V.; Sala, Salvatore la

doi:10.1002/ana.410400513

Cited by 211 publications

(117 citation statements)

References 38 publications

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“…Interestingly, the in vitro findings of the effects of the A53T and E46K mutations on ␣-syn polymerization are consistent with pathogenesis in human subjects. Patients with the A53T mutation have an earlier age of disease onset (average age of onset, 45 years) (10,13,14,55,56) than those carrying the E46K mutation (average age of onset, 60 years) (18).…”

Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 99%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

346

312

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The identification of a novel mutation (E46K) in one of the KTKEGV-type repeats in the amino-terminal region of ␣-synuclein suggests that this region and, more specifically, Glu residues in the repeats may be important in regulating the ability of ␣-synuclein to polymerize into amyloid fibrils. It was demonstrated that the E46K mutation increased the propensity of ␣-synuclein to fibrillize, but this effect was less than that of the A53T mutation. The substitution of Glu 46 for an Ala also increased the assembly of ␣-synuclein, but the polymers formed can have different ultrastructures, further indicating that this amino acid position has a significant effect on the assembly process. The effect of residue Glu 83 in the sixth repeat of ␣-synuclein, which lies closest to the amino acid stretch critical for filament assembly, was also studied. Mutation of Glu 83 to a Lys or Ala increased polymerization but perturbed some of the properties of mature amyloid. These results demonstrated that some of the Glu residues within the repeats can have significant effects on modulating the assembly of ␣-synuclein to form amyloid fibrils. The greater effect of the A53T mutation, even when compared with what may be predicted to be a more dramatic mutation such as E46K, underscores the importance of protein microenvironment in affecting protein structure. Moreover, the relative effects of the A53T and E46K mutations are consistent with the age of onset of disease. These findings support the notion that aberrant ␣-synuclein polymerization resulting in the formation of pathological inclusions can lead to disease.

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Section: E46k Mutation In ␣-Synuclein Increases Amyloid Formationmentioning

confidence: 99%

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Greenbaum

Graves

Mishizen-Eberz

et al. 2005

Journal of Biological Chemistry

346

312

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“…An increasing number of families have been described with apparent Mendelian inheritance of PD (Spellman, 1962 ;Wszolek et al 1995 ;Golbe et al 1996)]. Some of these families have atypical clinical features such as amyotrophy and dementia, but others more closely resemble sporadic PD clinically and pathologically and may provide important clues to understanding of the aetiology of the sporadic form of the disease.…”

Section: Family Studiesmentioning

confidence: 99%

Genetics of Parkinsonism: a review

VAUGHAN¹,

DAVIS²,

WOOD³

2001

Annals of Human Genetics

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Idiopathic Parkinson's disease (IPD), a progressive neurodegenerative disorder, is a common cause of disability. No current therapies modify disease progression. The pathological hallmarks are the presence of Lewy bodies and massive loss of dopaminergic neurons in the pars compacta of the substantia nigra. Two genes (SNCA and parkin) as well as two gene loci have now been implicated in the pathogenesis of familial PD. These represent significant progress in our understanding of the disease, considering the rarity of large families, low heritability in the general population and genetic heterogeneity. Mutations in a further gene, UCHL1, have been described in familial PD although the evidence for its role in PD is less clear. Knowledge of the genes described in PD to date should help to define molecular mechanisms of neurodegeneration in PD, as well as in other diseases where defects in protein handling may be a common feature. Nigral degeneration with Lewy body formation and the resulting clinical picture of PD may represent a final common pathway of a multifactorial disease process in which both environmental and genetic factors have a role. This review discusses the major advances in the field to date and illustrates how the existence of genetic factors has now become firmly established.

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“…As might be expected, different mutations in a single gene exhibit clinical and neuropathological variability. For example, individuals with A53T [12,16,24,25,29,39], E46K [46] or copy-number [13][14]32] mutations at SNCA have different phenotypes. However, it is striking that a single mutation also shows variability in the age of disease onset, rate of disease progression and duration, and neuropathology.…”

Section: Introductionmentioning

confidence: 99%

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

et al. 2008

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Individuals with familial Parkinson's disease (PD) due to a monogenic defect can show considerable clinical and neuropathological variability. To identify factors underlying this variability, histopathological analysis was performed in two clinically different A53T α-synuclein heterozygotes from Family H, a multigenerational α-synuclein A53T kindred. To determine whether additional genetic factors could contribute to phenotypic variability, Family H and another multigenerational A53T kindred were analyzed for parkin polymorphisms. We identified a previously described variant in parkin exon 4 associated with increased PD risk (S167N). The two A53T heterozygotes had markedly different neuropathology and different parkin genotypes: A N167 homozygote had early onset rapidly progressive disease, early dementia, myoclonus and sleep disorder, while a S167 homozygote had late onset, slowly progressive disease and late dementia. Both had brainstem, cortical, and intraneuritic Lewy bodies (LB). The N167 individual had widespread cortical neurofibrillary degeneration, while the S167 individual had only medial temporal lobe neurofibrillary degeneration. The N167 individual had severe neuronal loss in CA2 associated with Lewy neurites (LN), while the S167 individual had severe neuronal loss in CA1 associated with TDP-43 immunoreactive neuronal inclusions. These findings implicate TDP-43 in the pathology of familial PD and suggest that parkin may act as a modifier of the A53T α-synuclein phenotype of familial PD. Furthermore, they suggest a mechanism by which a rare genetic variant that is associated with a minor increase of PD risk in the heterozygous state may, in the homozygous state, exacerbate a disease phenotype associated with a highly penetrant dominant allele.

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Clinical genetic analysis of Parkinson's disease in the contursi kindred

Cited by 211 publications

References 38 publications

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

The E46K Mutation in α-Synuclein Increases Amyloid Fibril Formation

Genetics of Parkinsonism: a review

Clinical, neuropathological and genotypic variability in SNCA A53T familial Parkinson’s disease

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