PINK1 homozygous W437X mutation in a patient with apparent dominant transmission of Parkinsonism
ABSTRACT We analyzed the PINK1 gene in 58 patients with early-onset Parkinsonism and detected the homozygous mutation W437X in I patient. The clinical phenotype was characterized by early onset (22 years of age), good response to levodopa, early fluctuations and dyskinesias, and psychiatric symptoms. The mother, heterozygote for W437X mutation, was affected by Parkinson's disease and 3 further relatives were reported affected, according to an autosomal dominant transmission. (C) 2006 Movement Disorder Society.
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- "On the other hand, FH and AAO may be unreliable parameters; a better understanding of the pattern of inheritance, penetrance, and carrier frequency are needed to interpret the significance of these single heterozygous mutations. Apparently autosomal dominant (AD) forms of inheritance have also been noted [Criuscolo et al., 2006]. All these data point to the possibility that these heterozygous mutations may be pathogenic in an AD manner or may act as strong genetic risk factors in sporadic EOPD (as cases #33 and #34). "
ABSTRACT: Mutations in PARK2, PINK1, and DJ-1 have been associated with autosomal recessive early-onset Parkinson's disease. Here, we report the prevalence of sequence and structural mutations in these three main recessive genes in Mexican Mestizo patients. The complete sequences of these three genes were analyzed by homo/heteroduplex DNA formation and direct sequencing; exon dosage was determined by multiplex ligation-dependent probe amplification and real-time PCR in 127 patients belonging to 122 families and 120 healthy Mexican Mestizo controls. All individuals had been previously screened for the three most common LRRK2 mutations. The presence of two mutations in compound heterozygous or homozygous genotypes was found in 16 unrelated patients, 10 had mutations in PARK2, six in PINK1, and none in DJ-1. Two PARK2-PINK1 and one PARK2-LRRK2 digenic cases were observed. Novel mutations were identified in PARK2 and PINK1 genes, including PINK1 duplication for the first time. Exon dosage deletions were the most frequent mutations in PARK2 (mainly in exons 9 and 12), followed by those in PINK1. The high prevalence of heterozygous mutations in PARK2 (12.3%) and the novel heterozygous and homozygous point mutations in PINK1 observed in familial and sporadic cases from various states of Mexico support the concept that single heterozygous mutations in recessive Parkinson's disease genes play a pathogenic role. These data have important implications for genetic counseling of Mexican Mestizo patients with early-onset Parkinson's disease. The presence of digenic inheritance underscores the importance of studying several genes in this disease. A step-ordered strategy for molecular diagnosis is proposed. © 2014 Wiley Periodicals, Inc.American Journal of Medical Genetics Part B Neuropsychiatric Genetics 04/2014; 165(3). DOI:10.1002/ajmg.b.32228 · 3.27 Impact Factor
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- "Most recessive alleles result in the absence of the encoded protein or inactive protein and consequently in a loss of function. Homozygous or heterozygous mutations in the recessive genes parkin (PARK2), PINK1 (PARK6), and DJ-1 (PARK7) are unequivocally associated with a heritable early age at onset, in most cases before age 40, and no atypical signs   . Furthermore , autosomal recessive PD is characterized by: (1) slowly progressive disease course; (2) excellent response to L-DOPA, despite early L-DOPA induced dyskinesias; and (3) minimal cognitive decline and dysautonomia. "
ABSTRACT: Parkinson disease (PD) is a chronic and progressive neurological disease associated with a loss of dopaminergic neurons. In most cases the disease is sporadic but genetically inherited cases also exist. One of the major pathological features of PD is the presence of aggregates that localize in neuronal cytoplasm as Lewy bodies, mainly composed of α-synuclein (α-syn) and ubiquitin. The selective degeneration of dopaminergic neurons suggests that dopamine itself may contribute to the neurodegenerative process in PD. Furthermore, mitochondrial dysfunction and oxidative stress constitute key pathogenic events of this disorder. Thus, in this review we give an actual perspective to classical pathways involving these two mechanisms of neurodegeneration, including the role of dopamine in sporadic and familial PD, as well as in the case of abuse of amphetamine-type drugs. Mutations in genes related to familial PD causing autosomal dominant or recessive forms may also have crucial effects on mitochondrial morphology, function, and oxidative stress. Environmental factors, such as MPTP and rotenone, have been reported to induce selective degeneration of the nigrostriatal pathways leading to α-syn-positive inclusions, possibly by inhibiting mitochondrial complex I of the respiratory chain and subsequently increasing oxidative stress. Recently, increased risk for PD was found in amphetamine users. Amphetamine drugs have effects similar to those of other environmental factors for PD, because long-term exposure to these drugs leads to dopamine depletion. Moreover, amphetamine neurotoxicity involves α-syn aggregation, mitochondrial dysfunction, and oxidative stress. Therefore, dopamine and related oxidative stress, as well as mitochondrial dysfunction, seem to be common links between PD and amphetamine neurotoxicity.Free Radical Biology and Medicine 08/2012; 53(9):1791-806. DOI:10.1016/j.freeradbiomed.2012.08.569 · 5.71 Impact Factor
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- "A blood sample from his healthy mother was not available but, as a consequence of the genetic status of the proband, she was determined to be an obligated heterozygote. A similar pseudodominant condition has previously been reported in a homozygous patient carrying the W437X mutation  whose heterozygous mother was affected. The question of whether single heterozygous mutations in the recessive genes parkin and PINK1 are implicated in the development of the disease is still under debate. "
ABSTRACT: Mutations in the PINK1 gene represent the second most frequent cause of early-onset Parkinson's disease (EOPD). One or two mutated alleles were also reported in some sporadic or familial patients suffering from late-onset Parkinson's disease (LOPD). We aimed at assessing the frequency of mutations in this gene in our population. We performed a sequence analysis of PINK1 in 115 patients diagnosed with Parkinson's disease (PD) from southern Italy, including 93 sporadic cases with EOPD, 9 familial cases with EOPD, and 13 familial cases with LOPD. Three known homozygous mutations (Q456X, W437X, Q126P), corresponding to a 2.6% of all cases, were found. In particular, one mutation was detected among the sporadic cases (1.0%), one mutation among the familial early-onset patients (11.1%) and one mutation among the familial late-onset patients (7.7%). In addition, we found two heterozygous mutations (E476K, R207Q) among the sporadic patients. Only one mutation (R207Q) had not been previously described. Our results assess the role played by PINK1 in EOPD in southern Italy and illustrate the existence of mutations in this gene also in the late-onset form of the disease.Parkinsonism & Related Disorders 09/2011; 18(5):651-3. DOI:10.1016/j.parkreldis.2011.08.017 · 4.13 Impact Factor