Early-onset parkinsonism associated with PINK1 mutations: frequency, genotypes, and phenotypes.
OBJECTIVE
To assess the prevalence, nature, and associated phenotypes of PINK1 gene mutations in a large series of patients with early-onset (<50 years) parkinsonism.


METHODS
The authors studied 134 patients (116 sporadic and 18 familial; 77% Italian) and 90 Italian controls. The whole PINK1 coding region was sequenced from genomic DNA; cDNA was analyzed in selected cases.


RESULTS
Homozygous pathogenic mutations were identified in 4 of 90 Italian sporadic cases, including the novel Gln456Stop mutation; single heterozygous truncating or missense mutations were found in another 4 Italian sporadic cases, including two novel mutations, Pro196Leu and Gln456Stop. Pathogenic mutations were not identified in the familial cases. Novel (Gln115Leu) and known polymorphisms were identified with similar frequency in cases and controls. In cases carrying single heterozygous mutation, cDNA analysis detected no additional mutations, and revealed a major pathogenic effect at mRNA level for the mutant C1366T/Gln456Stop allele. All patients with homozygous mutations had very early disease onset, slow progression, and excellent response to l-dopa, including, in some, symmetric onset, dystonia at onset, and sleep benefit, resembling parkin-related disease. Phenotype in patients with single heterozygous mutation was similar, but onset was later.


CONCLUSIONS
PINK1 homozygous mutations are a relevant cause of disease among Italian sporadic patients with early-onset parkinsonism. The role of mutations found in single heterozygous state is difficult to interpret. Our study suggests that, at least in some patients, these mutations are disease causing, in combination with additional, still unknown factors.
Bonifati
V
V
Department of Clinical Genetics, Erasmus MC Rotterdam, The Netherlands. v.bonifati@erasmusmc.nl
Rohé
C F
CF
Breedveld
G J
GJ
Fabrizio
E
E
De Mari
M
M
Tassorelli
C
C
Tavella
A
A
Marconi
R
R
Nicholl
D J
DJ
Chien
H F
HF
Fincati
E
E
Abbruzzese
G
G
Marini
P
P
De Gaetano
A
A
Horstink
M W
MW
Maat-Kievit
J A
JA
Sampaio
C
C
Antonini
A
A
Stocchi
F
F
Montagna
P
P
Toni
V
V
Guidi
M
M
Dalla Libera
A
A
Tinazzi
M
M
De Pandis
F
F
Fabbrini
G
G
Goldwurm
S
S
de Klein
A
A
Barbosa
E
E
Lopiano
L
L
Martignoni
E
E
Lamberti
P
P
Vanacore
N
N
Meco
G
G
Oostra
B A
BA
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D002648:Child; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000032:analysis / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D016678:Genome / Q000235:genetics; D005838:Genotype; D006801:Humans; D007558:Italy / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D020125:Mutation, Missense; D010300:Parkinson Disease / Q000453:epidemiology / Q000235:genetics* / Q000503:physiopathology; D010641:Phenotype; D011110:Polymorphism, Genetic / Q000235:genetics; D011494:Protein Kinases / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000099202:PTEN-Induced Putative Kinase
D018076:DNA, Complementary; D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase