Asha Kishore1, Ashwin Ashok Kumar Sreelatha2, Marc Sturm3, Felix von-Zweydorf4,5, Lasse Pihlstrøm6, Francesco Raimondi7, Rob Russell7, Peter Lichtner8, Moinak Banerjee9, Syam Krishnan1, Roopa Rajan1,10, Divya Kalikavil Puthenveedu1, Sun Ju Chung11, Peter Bauer3, Olaf Riess3, Christian Johannes Gloeckner4,5, Rejko Kruger12,13, Thomas Gasser12, Manu Sharma2. 1. Sree Chitra Tirunal Institute for Medical Science and Technology, Kerala, India. 2. Centre for Genetic Epidemiology, Institute for Clinical Epidemiology and Applied Biometry, University of Tübingen, Tübingen, Germany. 3. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany. 4. German Center for Neurodegenerative Diseases (DZNE), Tübingen, Germany. 5. Institute for Ophthalmic Research, Center for Ophthalmology, University of Tübingen, Tübingen, Germany. 6. Department of Neurology, Oslo University Hospital, Oslo, Norway. 7. Cell Networks, University of Heidelberg, Heidelberg, Germany. 8. Institute of Human Genetics, Helmholtz Zentrum München, Neuherberg, Germany. 9. Rajiv Gandhi Centre for Biotechnology, Kerala, India. 10. All India Institute for Medical Sciences, New Delhi, India. 11. Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea. 12. Center of Neurology, and Hertie Institute for Clinical Brain Research, University Hospital, Tübingen, Germany. 13. LCSB, Luxembourg Centre for Systems Biology, University of Luxembourg, and Centre Hospitalier de Luxembourg (CHL), Luxembourg.
Abstract
BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro.
BACKGROUND: Genetic variability in LRRK2 has been unequivocally established as a major risk factor for familial and sporadic forms of PD in ethnically diverse populations. OBJECTIVES: To resolve the role of LRRK2 in the Indian population. METHODS: We performed targeted resequencing of the LRRK2 locus in 288 cases and 298 controls and resolved the haplotypic structure of LRRK2 in a combined cohort of 800 cases and 402 controls in the Indian population. We assessed the frequency of novel missense variants in the white and East Asian population by leveraging exome sequencing and densely genotype data, respectively. We did computational modeling and biochemical approach to infer the potential role of novel variants impacting the LRRK2 protein function. Finally, we assessed the phosphorylation activity of identified novel coding variants in the LRRK2 gene. RESULTS: We identified four novel missense variants with frequency ranging from 0.0008% to 0.002% specific for the Indian population, encompassing armadillo and kinase domains of the LRRK2 protein. A common genetic variability within LRRK2 may contribute to increased risk, but it was nonsignificant after correcting for multiple testing, because of small cohort size. The computational modeling showed destabilizing effect on the LRRK2 function. In comparison to the wild-type, the kinase domain variant showed 4-fold increase in the kinase activity. CONCLUSIONS: Our study, for the first time, identified novel missense variants for LRRK2, specific for the Indian population, and showed that a novel missense variant in the kinase domain modifies kinase activity in vitro.
Authors: Giambattista Guaitoli; Francesco Raimondi; Bernd K Gilsbach; Yacob Gómez-Llorente; Egon Deyaert; Fabiana Renzi; Xianting Li; Adam Schaffner; Pravin Kumar Ankush Jagtap; Karsten Boldt; Felix von Zweydorf; Katja Gotthardt; Donald D Lorimer; Zhenyu Yue; Alex Burgin; Nebojsa Janjic; Michael Sattler; Wim Versées; Marius Ueffing; Iban Ubarretxena-Belandia; Arjan Kortholt; Christian Johannes Gloeckner Journal: Proc Natl Acad Sci U S A Date: 2016-06-29 Impact factor: 11.205
Authors: Sohan Punia; Madhuri Behari; Shyla T Govindappa; Pazhayannur V Swaminath; Sachi Jayaram; Vinay Goyal; Uday B Muthane; R C Juyal; B K Thelma Journal: Neurosci Lett Date: 2006-10-18 Impact factor: 3.046
Authors: Pablo Cingolani; Viral M Patel; Melissa Coon; Tung Nguyen; Susan J Land; Douglas M Ruden; Xiangyi Lu Journal: Front Genet Date: 2012-03-15 Impact factor: 4.599