Heterogeneous phenotype in a family with compound heterozygous parkin gene mutations.
BACKGROUND
Mutations in the parkin gene (PRKN) cause autosomal recessive early-onset Parkinson disease (EOPD).


OBJECTIVE
To investigate the presence of mutations in the PRKN gene in a white family with EOPD and the genotype-phenotype correlations.


METHODS
Twenty members belonging to 3 generations of the EOPD family with 4 affected subjects underwent genetic analysis. Direct genomic DNA sequencing, semiquantitative polymerase chain reaction, real-time quantitative polymerase chain reaction, and reverse-transcriptase polymerase chain reaction analyses were performed to identify the PRKN mutation.


RESULTS
Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were identified in 4 patients with early onset (at ages 30-38 years). Although heterozygous T240M and homozygous EX 5_6 del mutations in the PRKN gene have been previously described, this is, to our knowledge, the first report of these mutations in compound heterozygotes. The phenotype of patients was that of classic autosomal recessive EOPD characterized by beneficial response to levodopa, relatively slow progression, and motor complications. All heterozygous mutation carriers (T240M or EX 5_6 del) and a 56-year-old woman who was a compound heterozygous mutation carrier (T240M and EX 5_6 del) were free of any neurological symptoms.


CONCLUSIONS
Compound heterozygous mutations (T240M and EX 5_6 del) in the PRKN gene were found to cause autosomal recessive EOPD in 4 members of a large white family. One additional member with the same mutation, who is more than 10 years older than the mean age at onset of the 4 affected individuals, had no clinical manifestation of the disease. This incomplete penetrance has implications for genetic counseling, and it suggests that complex gene-environment interactions may play a role in the pathogenesis of PRKN EOPD.
Deng
Hao
H
Department of Neurology, Baylor College of Medicine, Houston, Tex 77030, USA.
Le
Wei-Dong
WD
Hunter
Christine B
CB
Ondo
William G
WG
Guo
Yi
Y
Xie
Wen-Jie
WJ
Jankovic
Joseph
J
D000328:Adult; D017668:Age of Onset; D000368:Aged; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D010300:Parkinson Disease / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017422:Sequence Analysis, DNA; D044767:Ubiquitin-Protein Ligases / Q000235:genetics*
D044767:Ubiquitin-Protein Ligases; C111567:parkin protein