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PINK1 heterozygous rare variants: prevalence, significance and phenotypic spectrum
Author(s) -
Marongiu Roberta,
Ferraris Alessandro,
Ialongo Tàmara,
Michiorri Silvia,
Soleti Francesco,
Ferrari Francesca,
Elia Antonio E.,
Ghezzi Daniele,
Albanese Alberto,
Altavista Maria Concetta,
Antonini Angelo,
Barone Paolo,
Brusa Livia,
Cortelli Pietro,
Martinelli Paolo,
Pellecchia Maria Teresa,
Pezzoli Gianni,
Scaglione Cesa,
Stanzione Paolo,
Tinazzi Michele,
Zecchinelli Anna,
Zeviani Massimo,
Cassetta Emanuele,
Garavaglia Barbara,
Dallapiccola Bruno,
Bentivoglio Anna Rita,
Valente Enza Maria
Publication year - 2008
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.20719
Subject(s) - heterozygote advantage , compound heterozygosity , biology , lrrk2 , genetics , mendelian inheritance , pink1 , parkinsonism , context (archaeology) , disease , odds ratio , phenotype , age of onset , allele , mutation , gene , medicine , apoptosis , paleontology , autophagy , mitophagy
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. © 2008 Wiley‐Liss, Inc.