Lrrk2 p.Q1111H substitution and Parkinson’s disease in Latin America

Abstract

Mutations in the LRRK2 gene are the most common genetic cause of Parkinson’s disease, with frequencies displaying a high degree of population-specificity. Although more than 100 coding substitutions have been identified, only seven have been proven to be highly penetrant pathogenic mutations. Studies however are lacking in non-white populations. Recently, Lrrk2 p.Q1111H (rs78365431) was identified in two affected Hispanic brothers and absent in 386 non-Hispanic white healthy controls. We therefore screened this variant in 1460 individuals (1150 PD patients and 310 healthy controls) from 4 Latin American countries (Peru, Chile, Uruguay and Argentina). In our case-control series from Peru and Chile we observed an increased frequency of Lrrk2 p.Q1111H in patients (7.9%) compared to controls (5.4%) although the difference did not reach significance (OR 1.38; p=0.10). In addition, the frequency of Lrrk2 p.Q1111H varied greatly between populations and further screening in a set of pure Amerindian and pure Spanish controls suggested that this variant likely originated in an Amerindian population. Further studies in other Latin American populations are warranted to assess its role as a risk factor for Parkinson’s disease. Screening in Parkinson’s disease patients from under-represented populations will increase our understanding of the role of LRRK2 variants in disease risk worldwide.

Structural and functional in silico analysis of LRRK2 missense substitutions

“…This is of particular interest when a gene is prone to show genetic variability that is not apparently associated with a disease caused by mutations in that same gene. This is the case of dardarin, which is responsible for familial forms of PD [2], but with a high degree of coding substitutions [41]. In line with this, we analyzed 20 amino acid substitutions that were reported to be pathogenic and 25 other coding substitutions that are allegedly polymorphisms.…”

Neurogenética en el Perú, ejemplo de investigación traslacional

“…La mutación G2019S en el gen LRRK2, considerada la mutación dominante más frecuente en población caucásica, fue reportada con muy baja frecuencia en una población de pacientes con EP peruanos (22) ; 2). El hallazgo inesperado de la alta frecuencia del polimorfismo Q1111H en el gen LRRK2 en población mestiza peruana, permitió desestimar este polimorfismo como un factor de riesgo para EP (23) ; 3). El descubrimiento de potenciales nuevas mutaciones asociadas a EP familiar, como la encontrada en tres hermanos portadores en el gen PARK2 en tres hermanos prtadores (24) ; y 4).…”

Genetics and genomics in Peru: Clinical and research perspective

“…Since 2007, as part of the Latin American Research Consortium on the Genetics of Parkinson's Disease (LARGE‐PD), the study of genetics of PD in Peruvian population contributed to increased knowledge of PD. The LARGE PD cohort in Peru facilitate the discovery of novel mutations in PARKIN (OMIM #602544) gene (Cornejo‐Olivas, Torres, et al, ) as well as addressing the frequency and genotype‐genotype correlations of pathogenic variants of the LRRK2 (OMIM #609007) gene in Mestizo population from Latin America (Cornejo‐Olivas et al, ; Mata et al, ).…”