Parkin-proven disease: common founders but divergent phenotypes.
OBJECTIVE
To compare and contrast clinical and genetic findings in six probands with parkinsonism with a parkin exon 3 438- to 477-bp deletion (Ex3Delta40) to search for evidence of a common founder.


METHODS
Clinical review, parkin gene sequencing, dosage studies, and high-resolution genotype/haplotype analysis were performed.


RESULTS
All subjects had two or more signs consistent with a diagnosis of possible or probable PD with age at onset younger than 45 years (mean +/- SD 29.3 +/- 10.2 years, range 16 to 42 years). Affected individuals were either homozygotes, compound heterozygotes, or Ex3Delta40 carriers with one normal parkin allele. Haplotype analysis revealed both Ex3Delta40 and Ex7 924 C-->T (R275W) mutations originated from common founders, the former most probably of Irish descent. Although three cases had Ex7 924 C-->T (R275W) and Ex3Delta40 mutations, their clinical presentation and mode of inheritance were variable.


CONCLUSIONS
Parkin mutations on common parkin haplotypes provide testable hypotheses of parkin function in genetically defined parkinsonism.
Lincoln
S
S
Neurogenetic Laboratories, Department of Neuroscience, Mayo Clinic, Jacksonville, FL 32224, USA.
Wiley
J
J
Lynch
T
T
Langston
J W
JW
Chen
R
R
Lang
A
A
Rogaeva
E
E
Sa
D S
DS
Munhoz
R P
RP
Harris
J
J
Marder
K
K
Klein
C
C
Bisceglio
G
G
Hussey
J
J
West
A
A
Hulihan
M
M
Hardy
J
J
Farrer
M
M
D000328:Adult; D005091:Exons / Q000235:genetics; D005260:Female; D018703:Founder Effect; D005808:Genes, Recessive; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D017384:Sequence Deletion; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein