PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum.
Heterozygous rare variants in the PINK1 gene, as well as in other genes causing autosomal recessive parkinsonism, have been reported both in patients and healthy controls. Their pathogenic significance is uncertain, but they have been suggested to represent risk factors to develop Parkinson disease (PD). The few large studies that assessed the frequency of PINK1 heterozygotes in cases and controls yielded controversial results, and the phenotypic spectrum is largely unknown. We retrospectively analyzed the occurrence of PINK1 heterozygous rare variants in over 1100 sporadic and familial patients of all onset ages and in 400 controls. Twenty patients and 6 controls were heterozygous, with frequencies (1.8% vs. 1.5%) not significantly different in the two groups. Clinical features of heterozygotes were indistinguishable to those of wild-type patients, with mean disease onset 10 years later than in carriers of two mutations but worse disease progression. A meta-analysis indicated that, in PINK1 heterozygotes, the PD risk is only slightly increased with a non significant odds ratio of 1.62. These findings suggest that PINK1 heterozygous rare variants play only a minor susceptibility role in the context of a multifactorial model of PD. Hence, their significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.
Marongiu
Roberta
R
IRCCS CSS-Mendel Institute, Rome, Italy.
Ferraris
Alessandro
A
Ialongo
Tàmara
T
Michiorri
Silvia
S
Soleti
Francesco
F
Ferrari
Francesca
F
Elia
Antonio E
AE
Ghezzi
Daniele
D
Albanese
Alberto
A
Altavista
Maria Concetta
MC
Antonini
Angelo
A
Barone
Paolo
P
Brusa
Livia
L
Cortelli
Pietro
P
Martinelli
Paolo
P
Pellecchia
Maria Teresa
MT
Pezzoli
Gianni
G
Scaglione
Cesa
C
Stanzione
Paolo
P
Tinazzi
Michele
M
Zecchinelli
Anna
A
Zeviani
Massimo
M
Cassetta
Emanuele
E
Garavaglia
Barbara
B
Dallapiccola
Bruno
B
Bentivoglio
Anna Rita
AR
Valente
Enza Maria
EM
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000595:Amino Acid Sequence; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005808:Genes, Recessive; D014644:Genetic Variation; D006579:Heterozygote; D006801:Humans; D007558:Italy; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010300:Parkinson Disease / Q000201:enzymology / Q000235:genetics*; D010641:Phenotype; D011494:Protein Kinases / Q000235:genetics*; D012189:Retrospective Studies; D017386:Sequence Homology, Amino Acid; D000099202:PTEN-Induced Putative Kinase
D011494:Protein Kinases; D000099202:PTEN-Induced Putative Kinase