PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

Abstract

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 significance should be kept distinct from that of homozygous/compound heterozygous mutations, that cause parkinsonism inherited in a mendelian fashion.

Mutations and mechanism: howPINK1may contribute to risk of sporadic Parkinson’s disease

“…Interestingly the median age of disease onset was significantly earlier in the PINK1 hets, compared to non-carrier status (59yrs vs 64 yrs, p=0.012). These findings are in contrast to the previous largest meta-analysis [Marongiu et al 2008] that studied 1100 PD patients and 400 controls for het variants in the PINK1 gene and reported no significant difference in frequencies (1.8% vs 1.5%) between cases and controls. However this was a smaller study and considered all PINK1 variants rather than an association with only the p.G411S variant.…”

Syndromic parkinsonism and dementia associated with OPA1 missense mutations

“…Because previous studies have implicated single heterozygous mutations in PARK2 and PINK1 as possible risk factors for developing parkinsonism,51 we performed a comprehensive mutation analysis of both genes in our patients, but failed to identify pathogenic variants. Notably, a direct link was recently established between Parkin and OPA1, through linear ubiquitination of NF‐kB essential modulator, which upregulates the expression of OPA1, promoting mitochondrial integrity and protecting from stress‐induced cell death 52.…”

Clinically reported heterozygous mutations in the PINK1 kinase domain exert a gene dosage effect

“…Subsequently, a 1 to 8% mutation frequency has been reported in most early onset and/or familial cohorts [reviewed in Klein et al, 2007;Marongiu et al, 2008]. Interestingly, a number of single heterozygous PINK1 mutations (primarily in the serine/ threonine kinase domain) have been found in both patients and healthy controls [reviewed in Klein et al, 2007;Marongiu et al, 2008]. While an underlying haploinsufficiency is a possible mechanism, their role in pathogenicity has been debated due to divergent supporting evidence Marongiu et al, 2008].…”

“…Valente et al [2004] first identified two homozygous PINK1 mutations in three consanguineous PARK6 families. Subsequently, a 1 to 8% mutation frequency has been reported in most early onset and/or familial cohorts [reviewed in Klein et al, 2007;Marongiu et al, 2008]. Interestingly, a number of single heterozygous PINK1 mutations (primarily in the serine/ threonine kinase domain) have been found in both patients and healthy controls [reviewed in Klein et al, 2007;Marongiu et al, 2008].…”

“…Among these genes, phosphatase and tensin homolog (PTEN)-induced kinase 1 (PINK1, PARK6; MIM] 605909) is the second most common cause of recessive and early onset parkinsonism Marongiu et al, 2008;Tan and Skipper, 2007;Valente et al, 2004]. Valente et al [2004] first identified two homozygous PINK1 mutations in three consanguineous PARK6 families.…”