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mutations, including single heterozygous mutation, and in recent months, over 10 replication studies have
for DJ-1 in both familial and sporadic parkinsonism, provided conflicting data, casting considerable doubt
especially in large population samples. Moreover, in on the causal role of GIGYF2. [129] In addition, a pooled
a recent complete mutational analysis of DJ-1 coding analysis of over 4,500 PD and 5,500 controls revealed
sequence in a large cohort of familial and sporadic PD that the estimated frequency of GIGYF2 mutations in
cases from 12 countries, none had causative mutation the entire replication cohort was only about 0.001%. [127]
in DJ-1, suggesting its mutations are very rare in either Furthermore, the presence of mutations in healthy
familial or in sporadic parkinsonism. [113] population controls or within asymptomatic family
members of PD patients argues against causality even
UCH‑L1 if longitudinal data are not available. Thus, unless
The UCH‑L1 gene (PARK5) encodes the ubiquitin new information emerges to suggest otherwise, it is
carboxy-terminal hydrolase L1, which is a component reasonable to conclude that GIGYF2 does not play a
of LB and possesses both a hydrolase activity to generate major role in PD.
the ubiquitin monomer and a ligase activity to link
ubiquitin molecules to tag proteins for disposal. [114] The VPS35
detection of an Ile93Met mutation in the UCH-L1 gene The most recently described cause of monogenic PD
in a German family with autosomal dominant PD [115] is the mutations of a gene encoding vacuolar protein
suggested a role for an impaired ubiquitin-proteasomal sorting-associated protein 35 (VPS35), which were
activity in PD pathogenesis. In contrast, a Ser18Tyr identified by the next-generation of sequencing
polymorphism affecting mainly the ligase activity has technique. [130,131] Vilariño-Güell et al. [130] described the
been suggested to have a protective effect in PD in identification of the p.D620N mutation in VPS35 within
some association studies. [116] However, a subsequent affected members of a Swiss kindred and three other
large case-control study involving 3,044 PD cases and families with late-onset, autosomal dominant PD, and
3,252 controls, failed to replicate the association. [117] in one sporadic PD case. At the same time, Zimprich
et al. [131] published the identification of the p.D620N
Omi/HtrA2 mutation in a large multigenerational Austrian family
The gene Omi/HtrA2 (PARK13) encodes a serine-protease with PD and in two additional families screened for
with pro-apoptotic activity containing a mitochondrial VPS35 mutations. Both groups also identified additional
targeting sequence at its N-terminal region. [118] Several mutations in VPS35; however, the pathogenicity of
lines of evidence in the literature support a role for these additional variants remains unknown. Moreover,
Omi/HtrA2 in neurodegeneration. [119,120] The first VPS35 mutations have been detected only in whites
pathogenic mutation (G399S) a risk variant (A141S) with PD. Studies in both Chinese and Japanese have
for PD were identified in a German cohort. [121] excluded an association between VPS35 mutations and
However, a later case-control study screening the sporadic PD. [132-134]
whole coding region of Omi/HtrA2 revealed that
neither of the two variants was overrepresented in the PLA2G6
patients. [122] Although another mutation, R404W, was Mutations in phospholipase A2, group VI (PLA2G6) [135]
found in Belgian PD patients, [123] it is not clear whether usually cause an early-onset recessive degenerative
it is associated with PD patients in other populations. disorder with spasticity, ataxia and dystonia; however,
Further, the most recent large-scale analysis of the later adult onset forms of the disease can present with
five most informative SNPs spanning the Omi/HtrA2 a dystonia predominant parkinsonism. [136] The patients
gene in a cohort of 6,378 cases and 8,880 controls with PLA2G6 homozygous mutations presented in
from 20 sites worldwide again confirmed the lacking their 20s with slowly progressive gait problems,
of association of Omi/HtrA2 variants with PD. [124] clumsiness, imbalance, hand tremor, cognitive decline
Therefore, the genetic basis for the involvement of and dysarthria. Most patients with Parkinsonism are
Omi/HtrA2 is still not conclusive at this point. Levodopa-responsive at first, but this usually lasts only
1-2 years. PLA2G6 mutations have been screened for
GIGYF2 both early- and late-onset PD. Although SNPs have
Recently, it has been proposed that the GIGYF2 gene been identified in PD patients, none of these has been
corresponds to the PARK11 locus causes a form convincingly associated with the risk for PD. [137,138]
of autosomal-recessive familial PD. [125,126] In two
independent French and Italian familial PD populations, EIF4G1
10 changes in 16 unrelated PD patients were found Most recently, translation initiator mutations in
in the shortest form of GIGYF2, yielding a mutation EIF4G1 were genetically linked to autosomal dominant
frequency of 6.4%. [127] However, no disease-causing late-onset PD with brainstem Lewy body pathology. [139]
mutations were found in other European populations [128] EIF4G1 is a central component of the EIF4F complex

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