The discovery of LRRK2 p.R1441S, a novel mutation for Parkinson's disease, adds to the complexity of a mutational hotspot.
Mutations in the LRRK2 gene result in autosomal dominant, late onset Parkinson's disease (PD). Three such mutations (p.R1441C, p.R1441G, and p.R1441H) are known to occur within codon 1441, and haplotype analyses indicate that each one has arisen independently on multiple occasions. We sequenced the entire coding region of 18 casual genes for PD or other parkinsonian neurodegenerative disorders in the proband of a family with autosomal dominant PD. We discovered a new missense mutation in the LRRK2 gene, c.4321C>A (p.R1441S). The mutation was predicted to be highly deleterious in silico (Combined Annotation Dependent Depletion score of 25.5) and segregated with disease in the pedigree. The clinical characteristics of affected family members were similar to those described in PD families with other mutations in LRRK2 codon 1441 and included resting tremor, rigidity, bradykinesia, unilateral onset, and a good response to levodopa. Age at onset ranged from 41 to 76. Two of the affected members of the pedigree underwent detailed, longitudinal neuropsychological testing, and both displayed evidence of mild cognitive deficits at or slightly preceding the onset of motor symptoms. LRRK2 p.R1441S represents the fourth pathogenic mutation observed within codon 1441 and its discovery adds to the remarkable complexity of a mutational hotspot within the ROC domain of the LRRK2 protein. © 2016 Wiley Periodicals, Inc.
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
Ignacio F
IF
Mata
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
Marie Y
MY
Davis
Department of Medicine, University of Michigan, Ann Arbor, Michigan.
Alexis N
AN
Lopez
Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.|Department of Pathology, University of Washington, Seattle, Washington.
Michael O
MO
Dorschner
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.
Erica
E
Martinez
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
Dora
D
Yearout
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Psychiatry and Behavioral Sciences, University of Washington, Seattle, Washington.
Brenna A
BA
Cholerton
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
Shu-Ching
SC
Hu
Department of Epidemiology, University of California, Irvine, California.
Karen L
KL
Edwards
Veterans Affairs Puget Sound Health Care System, Seattle, Washington.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington.
Thomas D
TD
Bird
Veterans Affairs Puget Sound Health Care System, Seattle, Washington. zabetian@u.washington.edu.|Department of Neurology, University of Washington School of Medicine, Seattle, Washington. zabetian@u.washington.edu.
Cyrus P
CP
Zabetian
D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006239:Haplotypes; D006801:Humans; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D012307:Risk Factors
C495280:LRRK2 protein, human; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
genetics; movement disorders; neuropsychological