Whole gene deletion and splicing mutations expand thePINK1 genotypic spectrum

Marongiu, Roberta; Brancati, Francesco; Antonini, Angelo; Ialongo, Tàmara; Ceccarini, Caterina; Scarciolla, Oronzo; Capalbo, Anna; Benti, Riccardo; Pezzoli, Gianni; Dallapiccola, Bruno; Goldwurm, Stefano; Valente, Enza Maria

doi:10.1002/humu.9472

Cited by 67 publications

(47 citation statements)

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“…In our series, these are the only mutations that have been reported also in homozygous or compound heterozygous patients (Bonifati et al, 2005;Hedrich et al, 2006;Ibanez et al, 2006;Zadikoff et al, 2006;Marongiu et al, 2007). All other variants were missense changes that were located across the entire gene ( Figure 1, panel A).…”

Section: Pink1 Heterozygous Rare Variantsmentioning

confidence: 51%

“…We identified only two clearly pathogenic mutations (c. 1366C>T, p.Q456X and g.15445_15467del23), that have been shown to result in nonsense-mediated mRNA decay or the production of a truncated protein (Grunewald et al, 2007;Marongiu et al, 2007). In our series, these are the only mutations that have been reported also in homozygous or compound heterozygous patients (Bonifati et al, 2005;Hedrich et al, 2006;Ibanez et al, 2006;Zadikoff et al, 2006;Marongiu et al, 2007).…”

Section: Pink1 Heterozygous Rare Variantsmentioning

confidence: 61%

“…In the lack of long term follow-up studies, one way to look at this problem is to study large recessive pedigrees with homozygous or compound heterozygous mutations segregating in affected subjects, in which several relatives are in fact heterozygous for one mutation. In published families, the vast majority of heterozygotes are healthy, often including subjects old enough to have manifested the disease (Wu et al, 2002;Munhoz et al, 2004;Valente et al, 2004a;Marongiu et al, 2007). Yet, few Parkin and PINK1 pedigrees have been described in which some heterozygous relatives received a diagnosis of possible, probable or even definite PD Criscuolo et al, 2006;Hedrich et al, 2006).…”

Section: Discussionmentioning

confidence: 99%

“…with an affected uncle), were defined as "unclear inheritance". Detailed clinical data of heterozygotes were collected from clinical charts for comparison with two groups: 1) patients carrying two PINK1 mutations (n=10), including the two probands and four affected relatives from the original PARK6 Italian families (Valente et al, 2004a) and other four subsequently identified cases (Valente et al, 2004b;Marongiu et al, 2007;unpublished data); 2) a subgroup of 320 wild-type patients for whom full medical records were available, that was representative of the whole mutation negative group in terms of age at onset (50.4 ± 11.5 vs. 50.1 ± 11.3 years) and disease duration (11.6 ± 6.7 vs. 11.3 ± 6.5 years).…”

Section: Patientsmentioning

confidence: 99%

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PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

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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.

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Section: Pink1 Heterozygous Rare Variantsmentioning

confidence: 51%

Section: Pink1 Heterozygous Rare Variantsmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 99%

Section: Patientsmentioning

confidence: 99%

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PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

et al. 2008

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“…The largest heterozygous deletion published so far includes the entire PINK1 gene and spans for 56 kb [92]. This deletion also partly involves two neighbouring genes and two highly similar AluJo repeat sequences.…”

Section: Pink1mentioning

confidence: 99%

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Cognata¹,

D’Agata²,

Cavalcanti³

et al. 2016

Challenges in Parkinson's Disease

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Parkinson's disease (PD), the second most common progressive neurodegenerative disorder, was long believed to be a non-genetic sporadic origin syndrome. The identification of distinct genetic loci responsible for rare Mendelian forms of PD has represented a revolutionary breakthrough, allowing to discover novel mechanisms underlying this debilitating still incurable condition. Along with single-nucleotide polymorphisms (SNPs), other kinds of DNA molecular defects have emerged as significant disease-causing mutations, including large chromosomic structural rearrangements and copy number variations (CNVs). Due to their size variability and to the different sensitivity and resolution of detection methodologies, CNVs constitute a particular challenge in genetic studies and the pathogenetic or susceptibility impact of specific CNVs on PD is currently under debate. In this chapter, we will review the current literature and bioinformatic data describing the involvement of CNVs on PD pathobiology. We will discuss the recently highlighted role of PARK2 heterozygous CNVs, the possible common founder effects of PD gene rearrangements and the importance to map genetic breakpoints. We will also add a summary about the current available molecular methods and bioinformatics web resources to detect and interpret CNVs. Assessing the global genome-wide burden of large CNVs and elucidating the role of de novo rare structural variants on PD may reveal new candidate genes and consequently ameliorate diagnosis and counselling of mutations carriers.

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Expanding CEP290 mutational spectrum in ciliopathies

Travaglini¹,

Brancati²,

Attié‐Bitach³

et al. 2009

American J of Med Genetics Pt A

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Ciliopathies are an expanding group of rare conditions characterised by multiorgan involvement, that are caused by mutations in genes encoding for proteins of the primary cilium or its apparatus. Among these genes, CEP290 bears an intriguing allelic spectrum, being commonly mutated in Joubert syndrome and related disorders (JSRD), Meckel syndrome (MKS), Senior-Loken syndrome and isolated Leber congenital amaurosis (LCA). Although these conditions are recessively inherited, in a subset of patients only one CEP290 mutation could be detected. To assess whether genomic rearrangements involving the CEP290 gene could represent a possible mutational mechanism in these cases, exon dosage analysis on genomic DNA was performed in two groups of CEP290 heterozygous patients, including five JSRD/MKS cases and four LCA, respectively. In one JSRD patient, we identified a large heterozygous deletion encompassing CEP290 C-terminus, that resulted in marked reduction of mRNA expression. No copy number alterations were identified in the remaining probands. The present work expands the CEP290 genotypic spectrum to include multiexon deletions. Although this mechanism does not appear to be frequent, screening for genomic rearrangements should be considered in patients in whom a single CEP290 mutated allele was identified.

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Whole gene deletion and splicing mutations expand thePINK1 genotypic spectrum

Cited by 67 publications

References 14 publications

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

PINK1heterozygous rare variants: prevalence, significance and phenotypic spectrum

Genetics of Parkinson’s Disease: The Role of Copy Number Variations

Expanding CEP290 mutational spectrum in ciliopathies

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