New contribution on the <i>LRRK2</i> G2019S mutation associated to Parkinson’s disease: age estimation of a common founder event of old age in Moroccan Berbers

Abstract

-Background:The LRRK2 G2019S mutation is an important genetic determinant of Parkinson's disease (PD) across the world that occurs at an elevated frequency in North Africa. Aim: To estimate the date of the G2019S mutation in Berbers. Material and Methods: We determined the LRRK2 haplotypes in twenty-two G2019S carriers, mostly North Africans, and in one hundred twenty-four Arab, Moroccan Berber and Sephardi Jew controls, using seven microsatellite and two SNP genetic markers. Results: A single haplotype was detected, with some variations, in all mutation carriers. Using a maximum-likelihood method, we estimate that Moroccan Berbers with G2019S share a common ancestor who lived ~128 (95% CI 107-180) generations ago. Conclusion: Our conclusion is that the G2019S mutation of the LRRK2 gene originates 3,840 (95% CI 3,210-5,400) years ago in parkinsonian Moroccan Berbers patients.

Evidence for prehistoric origins of the G2019S mutation in the North African Berber population

“…Also considering an intergenerational time interval of 25 years and using the ESTIAGE program, Lesage and collaborators reported an age estimate of about 3000 years using data collected from 67 North African patients and 8 microsatellites (D12S2080 to D12S1301) [ 11 ]. However, the age estimate provided by Lucotte et al [ 16 ] was about 3200 years using 7 microsatellites (D12S2194 to D12S1048). In the first study, only 10 patients were of Moroccan origin and were considered Arabs, while in the second study, the authors focused on only 5 Berber- and 2 Arab-speaking patients of Moroccan origin, neither of which is representative of the Moroccan population.…”

“…Despite this ancient connection, it is unlikely that the G2019S mutation is of Sephardic Jewish origin because the studies comparing Sephardic to Berber carriers all point to a Berber origin of the mutation. Berbers showed the highest prevalence and incidence of the mutation as well as the shorter haplotype compared to Sephardic Jews [ 16 , 50 , 52 ]. However, a problem arises when we attempt to explain the high frequency of this mutation in the Ashkenazim population.…”

“…However, the most significant study carried out by Lesage et al on a large sample of patients belonging to several ethnicities, which suggested that haplotype 1 originated in a Near-Eastern founder at least 4000 years ago [ 11 ]. Finally, a recent study on North African patients concluded that the G2019S mutation originated in a Moroccan Berber patient who lived 3840 years ago [ 16 ].…”