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Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.

Suzanne Lesage 1 Etienne Patin 2 Christel Condroyer 1 Anne-Louise Leutenegger 3 Ebba Lohmann 1 Nir Giladi 4, 5 Anat Bar-Shira 6 Soraya Belarbi 7 Nassima Hecham 7 Pierre Pollak 8 Anne-Marie Ouvrard-Hernandez 9 Soraya Bardien 10 Jonathan Carr 10 Traki Benhassine 11 Hiroyuki Tomiyama 12 Caroline Pirkevi 13 Tarik Hamadouche 14 Cécile Cazeneuve 15 a Nazli Basak 13 Nobutaka Hattori 16 Alexandra Dürr 1, 15 Meriem Tazir 7 Avi Orr-Urtreger 5, 6 Lluis Quintana-Murci 17 Alexis Brice 1, 15, *
* Corresponding author
1 CRICM - Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière
2 Prévention et Thérapie Moléculaires des Maladies Infectieuses Humaines
3 Variabilité Génétique et Maladies Humaines
4 Movement Disorders Unit
5 The Sackler Faculty of Medicine
6 Genetic Institute
7 Service de Neurologie
8 Département de neurologie
9 Département de neurologie
10 Division of Neurology
11 Laboratoire de Biologie Cellulaire et Moléculaire
12 Department of Neurology
13 Neurodegeneration Research Laboratory
14 Laboratoire de biologie moléculaire
15 Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière]
16 Juntendo University School of Medicine
17 Epidémiologie et Physiopathologie des Virus Oncogènes
Abstract : Mutations in the leucine-rich-repeat kinase 2 (LRRK2) gene have been identified in families with autosomal dominant Parkinson's disease (PD) and in sporadic cases; the G2019S mutation is the single most frequent. Intriguingly, the frequency of this mutation in PD patients varies greatly among ethnic groups and geographic origins: it is present at <0.1% in East Asia, approximately 2% in European-descent patients and can reach frequencies of up to 15-40% in PD Ashkenazi Jews and North African Arabs. To ascertain the evolutionary dynamics of the G2019S mutation in different populations, we genotyped 74 markers spanning a 16 Mb genomic region around G2019S, in 191 individuals carrying the mutation from 126 families of different origins. Sixty-seven families were of North-African Arab origin, 18 were of North/Western European descent, 37 were of Jewish origin, mostly from Eastern Europe, one was from Japan, one from Turkey and two were of mixed origins. We found the G2019S mutation on three different haplotypes. Network analyses of the three carrier haplotypes showed that G2019S arose independently at least twice in humans. In addition, the population distribution of the intra-allelic diversity of the most widespread carrier haplotype, together with estimations of the age of G2019S determined by two different methods, suggests that one of the founding G2019S mutational events occurred in the Near East at least 4000 years ago.
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https://www.hal.inserm.fr/inserm-00522011
Contributor : Suzanne Lesage <>
Submitted on : Wednesday, September 29, 2010 - 12:35:58 PM
Last modification on : Thursday, August 27, 2020 - 3:10:05 PM
Long-term archiving on: : Friday, December 2, 2016 - 7:05:18 AM

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Suzanne Lesage, Etienne Patin, Christel Condroyer, Anne-Louise Leutenegger, Ebba Lohmann, et al.. Parkinson's disease-related LRRK2 G2019S mutation results from independent mutational events in humans.. Human Molecular Genetics, Oxford University Press (OUP), 2010, 19 (10), pp.1998-2004. ⟨10.1093/hmg/ddq081⟩. ⟨inserm-00522011⟩

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