LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8
ABSTRACT Pathogenic mutations in the leucine-rich repeat kinase 2 gene (LRRK2) have been found to cause typical, later-onset Parkinson disease (PD). Although G2019S is the most common mutation, other mutations have also been reported. It is critical to catalog the types of mutations found in LRRK2 that can cause PD, so as to provide insight regarding disease susceptibility and potential novel treatments.
We performed a comprehensive study of all 51 exons of the LRRK2 gene in one PD patient from each of 88 multiplex PD families who had the highest family-specific multipoint lod score at the LRRK2 locus from a cohort of 430 PD families without the G2019S mutation.
Five families (5.7%) harbored what seem to be novel, pathogenic mutations (L1795F, I1192V, E10K, E334K, Q1111H). Three of these apparent mutations were in known, functional domains of the LRRK2 protein, where other studies have also identified disease producing mutations. However, two of the novel variants were found in the N-terminal region of LRRK2, where no pathogenic substitutions have yet been reported. Similar to previous studies, all subjects with an LRRK2 mutation had classic symptoms of PD and typical, later age at onset.
We have identified five novel variants in LRRK2, with two of these in the N-terminal region of LRRK2, where no pathogenic substitutions have been previously reported. If confirmed to be causative, these mutations would broaden the potential mechanisms whereby mutations in LRRK2 result in Parkinson disease.
- SourceAvailable from: Jean-Marc Taymans
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- "c o m / l o c a t e / b b a p a p domains have been formally confirmed to segregate with PD . Variants in the LRR domain have also been reported (I1006M, R1067Q, S1096C, Q1111H, I1122V, L1165P, I1192V, S1228T & P1262A         ), however because these variants are rare, a segregation with disease has not been confirmed. "
ABSTRACT: Mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease. Much research effort has been directed towards the catalytic core region of LRRK2 composed of GTPase (ROC, Ras of complex proteins) and kinase domains and a connecting COR (C-terminus of ROC) domain. In contrast, the precise functions of the protein-protein interaction domains, such as the leucine-rich repeat (LRR) domain, are not known. In the present study, we modeled the LRRK2 LRR domain (LRR(LRRK2)) using a template assembly approach, revealing the presence of 14 LRRs. Next, we focused on the expression and purification of LRR(LRRK2) in Escherichia coli. Buffer optimization revealed that the protein requires the presence of a zwitterionic detergent, namely Empigen BB, during solubilization and the subsequent purification and characterization steps. This indicates that the detergent captures the hydrophobic surface patches of LRR(LRRK2) thereby suppressing its aggregation. Circular dichroism (CD) spectroscopy measured 18% α-helices and 21% β-sheets, consistent with predictions from the homology model. Size exclusion chromatography (SEC) and dynamic light scattering measurements showed the presence of a single species, with a Stokes radius corresponding to the model dimensions of a protein monomer. Furthermore, no obvious LRR(LRRK2) multimerization was detected via cross-linking studies. Finally, the LRR(LRRK2) clinical mutations did not influence LRR(LRRK2) secondary, tertiary or quaternary structure as determined via SEC and CD spectroscopy. We therefore conclude that these mutations are likely to affect putative LRR(LRRK2) inter- and intramolecular interactions.Biochimica et Biophysica Acta 03/2012; 1824(3):450-60. DOI:10.1016/j.bbapap.2011.12.009 · 4.66 Impact Factor
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- "In a comprehensive LRRK2 sequencing study of all 51 exons, Nichols and colleagues found several putative pathogenic variants in patients from 88 multiplex families, mostly of European-origin . A Glutamine to Histidine substitution (p.Q1111H; rs78365431), was identified in 2 Hispanic siblings; DNA was not available for any other family members and thus segregation analysis could not be performed. "
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.Parkinsonism & Related Disorders 05/2011; 17(8):629-31. DOI:10.1016/j.parkreldis.2011.05.003 · 4.13 Impact Factor
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- "The G2019S substitution (c.6055 G>A: Gly2019Ser) in exon 41 shows age-dependent, reduced penetrance (Healy et al., 2008; Hulihan et al., 2008). The G2019S mutation is present in several populations with a highly variable frequency according to the geographic / ethnic origin (Nichols et al., 2007). Although only found in 0.1% of PD cases in Asia (Tomiyama et al., 2006), this mutation is much more frequent in Europeans with 2%–6% of familial cases and 1%–2% of sporadic cases (Brice, 2005). "
ABSTRACT: Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease. A progressive movement disorder typified by the production of bradykinesia, tremor, rigidity, and impairment of postural reflexes, PD is characterized by a depletion of dopamine in the striatum. For the last decade, several Mendelian forms of PD have been identified. Mutations in these genes potentially lead to autosomal dominant (alpha-synuclein and LRRK2), or autosomal recessive PD (Parkin, PINK1, DJ1, and ATP13A2). This article will spotlight these six distinct genes unambiguously associated with Mendelian PD and the function of their encoded proteins.The Anatomical Record Advances in Integrative Anatomy and Evolutionary Biology 11/2009; 292(12):1893-901. DOI:10.1002/ar.20968 · 1.53 Impact Factor