LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8

W. C. Nichols, V. E. Elsaesser, N. Pankratz, M. W. Pauciulo, D. K. Marek, C. A. Halter, A. Rudolph, C. W. Shults, Tatiana Foroud

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Abstract

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Original languageEnglish
Pages (from-to)1737-1744
Number of pages8
JournalNeurology
Volume69
Issue number18
DOIs
StatePublished - Oct 2007

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Leucine
Parkinson Disease
Phosphotransferases
Mutation
Genes
Lod Score
Disease Susceptibility
Age of Onset
Exons

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

Nichols, W. C., Elsaesser, V. E., Pankratz, N., Pauciulo, M. W., Marek, D. K., Halter, C. A., ... Foroud, T. (2007). LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology, 69(18), 1737-1744. https://doi.org/10.1212/01.wnl.0000278115.50741.4e

LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. / Nichols, W. C.; Elsaesser, V. E.; Pankratz, N.; Pauciulo, M. W.; Marek, D. K.; Halter, C. A.; Rudolph, A.; Shults, C. W.; Foroud, Tatiana.

In: Neurology, Vol. 69, No. 18, 10.2007, p. 1737-1744.

Research output: Contribution to journalArticle

Nichols, WC, Elsaesser, VE, Pankratz, N, Pauciulo, MW, Marek, DK, Halter, CA, Rudolph, A, Shults, CW & Foroud, T 2007, 'LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8', Neurology, vol. 69, no. 18, pp. 1737-1744. https://doi.org/10.1212/01.wnl.0000278115.50741.4e
Nichols WC, Elsaesser VE, Pankratz N, Pauciulo MW, Marek DK, Halter CA et al. LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. Neurology. 2007 Oct;69(18):1737-1744. https://doi.org/10.1212/01.wnl.0000278115.50741.4e
Nichols, W. C. ; Elsaesser, V. E. ; Pankratz, N. ; Pauciulo, M. W. ; Marek, D. K. ; Halter, C. A. ; Rudolph, A. ; Shults, C. W. ; Foroud, Tatiana. / LRRK2 mutation analysis in Parkinson disease families with evidence of linkage to PARK8. In: Neurology. 2007 ; Vol. 69, No. 18. pp. 1737-1744.
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AU - Elsaesser, V. E.

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AU - Pauciulo, M. W.

AU - Marek, D. K.

AU - Halter, C. A.

AU - Rudolph, A.

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N2 - BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

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