PARK2 is an autosomal recessive familial PD caused by mutations of parkin. Clinical features of PARK2 were first described by Yamamura et al. (1973). They reported 16 patients (13 familial patients in 5 unrelated families and 3 sporadic cases); clinical features of 11 patients from the initial 4 families were essentially identical. Ages of onset were between 17 and 28 years in 10 out of 11 patients and 42 in the remaining one. All the patients showed tremor, rigidity, bradykinesia, and postural instability. Atypical features included sleep benefit, temporary improvement of parkinsonism after a nap or sleep, and dys-tonic postures in the feet during walking (talipes equinovarus). Dementia was absent.
These patients show good response to L-dopa but they frequently develop motor fluctuations (wearing off and dyskinesia) sooner than late onset PD patients; usually two to three years after the initiation of L-dopa. Since the gene analysis became possible, many atypical features have been reported. For instance, age of onset can be as late as 72 (Lincolon et al., 2003). Other atypical features reported include dementia (Benbuman et al., 2004), psychosis and behavioral problem (Kahn et al., 2003), cerebellar ataxia (Kuroda et al., 2001), peripheral neuropathy (Tassin et al., 1998; Okuma et al., 2003; Kahn et al., 2003), hyperhidrosis (Yamamura et al., 1998), orthostatic hypotension (Kahn et al., 2003), urinary urgency and impotence (Kahn et al., 2003), and hemiparkinsonism-
Fig. 2. Schematic presentation of exons of parkin and its exon rearrangements. summarized from the following literature, i.e., Hattori et al. (1998), Abbas et al. (1999), Lucking et al. (2000), Oliviera et al. (2003), and Hedrick et al. (2004). Broken lines indicate triplication, dotted lines duplication, and solid lines deletions of exons. UBL ubiquitin-like domain, RING RING domain, IBR in-between RINGs
Fig. 2. Schematic presentation of exons of parkin and its exon rearrangements. summarized from the following literature, i.e., Hattori et al. (1998), Abbas et al. (1999), Lucking et al. (2000), Oliviera et al. (2003), and Hedrick et al. (2004). Broken lines indicate triplication, dotted lines duplication, and solid lines deletions of exons. UBL ubiquitin-like domain, RING RING domain, IBR in-between RINGs hemiatrophy (Pramistaller et al., 2002) have been reported.
PARK2 is caused by mutations of parkin (Kitada et al., 1998), which has been mapped to the long arm of chromosome 6 at 6q25.2-q27. To date more than 30 different exon rearrangements (deletion, duplication, and triplication) (Fig. 2), 30 missense mutations, and 8 nonsense mutations, and close to 20 small deletions or insertions (Fig. 3) have been reported (Hattori et al., 1998; Abbas et al., 1999; Lucking et al., 2000; Oliviera et al., 2003; Hedrick et al., 2004). These numbers are still increasing. Usually PARK2 patients harbor either homozygous mutations or compound heterozygous mutations of parkin. But at times single heterozygous mutations are seen. According to our hand, approximately 20% of patients with parkin mutations were single heterozygotes, in that only one allele of parkin showed a mutation and we could not find the second mutation. Question is how they could have got the disease. As PARK2 is an autosomal recessive disorder, it is expected that both of parkin alleles are mutated. Although exact mechanism is not known, numbers of possibilities can be considered. For instance, single normal parkin may not be suffice to its complete function (haploin-sufficiency); mutated parkin protein in some way may interfere with the function of normal parkin protein (dominant-negative effect); single mutated parkin may predispose to late onset Lewy body-positive PD.
Parkin protein was found to be an ubiquitin-protein ligase (E3) of the ubiquitin system (Shimura et al., 2000). The ubiquitin-proteasome system (UPS) is an important intracellular proteolytic system responsible for wide variety of biologically important cellular processes, such as cell-cycle progression, signaling cascades, developmental programs, the protein quality control system, DNA repair, apoptosis, signal transduction, transcription,
M192 V M192L S1931
C253Y T240M T240R
R275W G328E R402C T415N C431F D280N
CI212G M R396G
R33X R50X E79X 87delG 101-2delAG
321-2insGT 220insGT 40bpdel 255delA (236-76) 535delG 202-3delAG 202delA
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