Screening for SNCA and LRRK2 mutations in Greek sporadic and autosomal dominant Parkinson's disease: identification of two novel LRRK2 variants

Xiromerisiou, Georgia; Hadjigeorgiou, George; Gourbali, V.; Johnson, Janel O.; Papakonstantinou, Ilias; Papadimitriou, Alexandros; Singleton, Andrew B.

doi:10.1111/j.1468-1331.2006.01551.x

Cited by 49 publications

(30 citation statements)

References 22 publications

(33 reference statements)

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“…1 presents the frequencies of LRRK2 G2019S mutations across the globe. 5,7,8,10,[12][13][14][15][16][18][19][20][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42] Our study has certain limitations. The studied cohort is relatively small and not all LRKK2 mutations or polymorphisms were analyzed.…”

Section: Discussionmentioning

confidence: 93%

Is the G2019S LRRK2 mutation common in all southern European populations?

Papapetropoulos¹,

Adi²,

Shehadeh³

et al. 2008

Journal of Clinical Neuroscience

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Section: Discussionmentioning

confidence: 93%

Is the G2019S LRRK2 mutation common in all southern European populations?

Papapetropoulos¹,

Adi²,

Shehadeh³

et al. 2008

Journal of Clinical Neuroscience

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“…The first was from Crete and was recruited through the Neurology Services of the University Hospital of Heraklion, 5 whereas the second was from Central Greece and was recruited from the Movement Disorder Clinics of the University Hospitals of Larissa (Thessaly) 14 and Patras (Northern Peloponnese). 15 The North American PD cohort was from Central California and was recruited through a population-based study 16 of the UCLA School of Public Health.…”

Section: Patients and Methods Patientsmentioning

confidence: 99%

Gain-of-function variant in GLUD2 glutamate dehydrogenase modifies Parkinson's disease onset

et al. 2009

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Parkinson's disease (PD), a common neurodegenerative disorder characterized by progressive loss of dopaminergic neurons and their terminations in the basal ganglia, is thought to be related to genetic and environmental factors. Although the pathophysiology of PD neurodegeneration remains unclear, protein misfolding, mitochondrial abnormalities, glutamate dysfunction and/or oxidative stress have been implicated. In this study, we report that a rare T1492G variant in GLUD2, an X-linked gene encoding a glutamate dehydrogenase (a mitochondrial enzyme central to glutamate metabolism) that is expressed in brain (hGDH2), interacted significantly with age at PD onset in Caucasian populations. Individuals hemizygous for this GLUD2 coding change that results in substitution of Ala for Ser445 in the regulatory domain of hGDH2 developed PD 6-13 years earlier than did subjects with other genotypes in two independent Greek PD groups and one North American PD cohort. However, this effect was not present in female PD patients who were heterozygous for the DNA change. The variant enzyme, obtained by substitution of Ala for Ser445, showed an enhanced basal activity that was resistant to GTP inhibition but markedly sensitive to modification by estrogens. Thus, a gain-of-function rare polymorphism in hGDH2 hastens the onset of PD in hemizygous subjects, probably by damaging nigral cells through enhanced glutamate oxidative dehydrogenation. The lack of effect in female heterozygous PD patients could be related to a modification of the overactive variant enzyme by estrogens. INTRODUCTIONParkinson's disease (PD) affects about 1.8% of people over the age of 65 years. 1 It is clinically characterized by tremor, rigidity and bradykinesia, which often occur along with disturbances of posture and gait. 2 About 80% of PD cases are sporadic, with males being more frequently affected than females (ratio¼1.5:1).The etiology of PD remains largely unknown, although interplay of environmental toxins with genetic susceptibility may be operational. The genetic hypothesis is supported by community-based studies showing that a substantial number of PD patients have similarly affected relatives. 3,4 This was also revealed by a PD study conducted by us on Crete, 5 an island of about 0.6 million people sharing the same genetic and cultural background and a common environment. Moreover, this study suggested an oligogenic model for PD, according to which disease-predisposing alleles from two or more genes need to be present in the same individual for the disorder to be expressed.With regard to the pathophysiology of PD, several hypotheses have been proposed in an attempt to explain the degeneration of dopaminergic neurons in this disorder. One of these suggests that mitochondrial dysfunction is involved, 6 a contention supported by the recent discovery of monogenetic forms of PD resulting from mutations of

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“…[18] Similarly, the analysis conducted in Greek population suggested that the mutations in the SNCA gene may not be playing role in causing PD. [19] Many studies conducted worldwide related to the pathogenicity of SNCA gene in PD reveal the lack of mutations. [20][21][22][23][24][25] India is known for high degree of inbreeding with its heterogynous population.…”

Section: Discussionmentioning

confidence: 99%