Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

Seki, Naomi; Takahashi, Yūji; Tomiyama, Hiroyuki; Rogaeva, Ekaterina; Murayama, Shigeo; Mizuno, Yoshikuni; Marras, Connie; Lang, Anthony E.; George-Hyslop, Peter St; Goto, Jun; Tsuji, Shoji

doi:10.1038/jhg.2011.79

Cited by 11 publications

(11 citation statements)

References 47 publications

(59 reference statements)

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“…3,4,6,7,17 Moreover, the frequency in Japanese patients also differs greatly from those of other Asian populations such as Taiwanese patients and mainland Chinese patients (0%). 3,8 Although the mutation frequency was expected to be lower than that of other pathogenic genes for ADPD, such as multiplication of SNCA 9,18 and point mutation of LRRK2, [19][20][21] VPS35 may be one of the most important genes in Japanese PD. Because we screened for only 7 reported variants, we cannot determine the exact frequency of VPS35 mutations in ADPD; we would need to analyze all 17 exons of VPS35 in ADPD patients to screen for other variants and to assess the incidence of all disease-associated VPS35 mutations.…”

Section: Discussionmentioning

confidence: 99%

VPS35 mutation in Japanese patients with typical Parkinson's disease

Ando

Funayama

et al. 2012

Movement Disorders

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Vacuolar protein sorting 35 (VPS35) was recently reported to be a pathogenic gene for late-onset autosomal dominant Parkinson's disease (PD), using exome sequencing. To date, VPS35 mutations have been detected only in whites with PD. The aim of the present study was to determine the incidence and clinical features of Asian PD patients with VPS35 mutations. We screened 7 reported nonsynonymous missense variants of VPS35, including p.D620N, known as potentially disease-associated variants of PD, in 300 Japanese index patients with autosomal dominant PD and 433 patients with sporadic PD (SPD) by direct sequencing or high-resolution melting (HRM) analysis. In addition, we screened 579 controls for the p.D620N mutation by HRM analysis. The p.D620N mutation was detected in 3 patients with autosomal dominant PD (1.0%), in 1 patient with SPD (0.23%), and in no controls. None of the other reported variants of VPS35 were detected. Haplotype analysis suggested at least 3 independent founders for Japanese patients with p.D620N mutation. Patients with the VPS35 mutation showed typical tremor-predominant PD. We report Asian PD patients with the VPS35 mutation. Although VPS35 mutations are uncommon in PD, the frequency of such mutation is relatively higher in Japanese than reported in other populations. In VPS35, p.D620N substitution may be a mutational hot spot across different ethnic populations. Based on the clinical features, VPS35 should be analyzed in patients with PD, especially autosomal dominant PD or tremor-predominant PD.

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Section: Discussionmentioning

confidence: 99%

VPS35 mutation in Japanese patients with typical Parkinson's disease

Ando

Funayama

et al. 2012

Movement Disorders

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“…The R1441H mutation appears to be pathogenic and confirms that this amino acid is a mutational hotspot [20]. The I1371V mutation seems to segregate with disease, but little is known about the functional consequences of this mutation [21]. Another mutation in the GTPase domain, N1437H, was recently found in a large Norwegian family with autosomal-dominant PD [22].…”

Section: Pathogenic Mutations In the Lrrk2 Gtpase Domainmentioning

confidence: 99%

LRRK2 GTPase dysfunction in the pathogenesis of Parkinson's disease

Xiong

Dawson

2012

Biochemical Society Transactions

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Mutations in the leucine-rich repeat kinase 2 gene (LRRK2) are the most frequent genetic cause of Parkinson’s disease (PD) and these mutations play important roles in sporadic PD. The LRRK2 protein contains GTPase and kinase domains and several protein-protein interaction domains. The kinase and GTPase activity of LRRK2 seem to be important in regulating LRRK2-dependent cellular signaling pathways. LRRK2’s GTPase and kinase domains may reciprocally regulate each other to direct LRRK2’s ultimate function. While most LRRK2 investigations are centered on LRRK2’s kinase activity, this review focuses on the function of LRRK2’s GTPase in LRRK2 physiology and pathophysiology.

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“…It is also been reported that head injury, well-water ingestion, rural living, middle-age obesity, and lack of exercise may have association with PD (Elbaz and Tranchant, 2007; Thacker et al, 2008). Recently, genetic studies have made great breakthrough in etiology of PD, revealing several genes that are closely linked to heritable PD, which accounts for about 10% PD cases (Paisán-Ruíz et al, 2004; Valente et al, 2004; Zimprich et al, 2004; Seki et al, 2011). How these different factors may function together in triggering PD remains unclear.…”

Section: Introductionmentioning

confidence: 99%

“…These include genes for SNCA, UCHL1, GIGYF2, HtrA2, LRRK2, PARK2, DJ1, PINK1 , and ATP13A2 (Kim and Choi, 2010; Seki et al, 2011). Leucine-rich repeat kinase 2 (LRRK2) and PINK1 are of particular interest because they are kinases and known to be involved in autophagy and mitophagy, two processes to which MEF2D have been linked (Paisán-Ruíz et al, 2004; Valente et al, 2004; Zimprich et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

Modulation of Neuronal Survival Factor MEF2 by Kinases in Parkinson’s Disease

Yin¹,

She²,

Li³

et al. 2012

Front. Physio.

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Parkinson’s disease (PD) is the second most common neurodegenerative disorder due to selective death of neurons in the substantia nigra pars compacta. The cause of cell death remains largely unknown. Myocyte enhancer factor 2 (MEF2) is a group of transcriptional factors required to regulate neuronal development, synaptic plasticity, as well as survival. Recent studies show that MEF2 functions are regulated in multiple subcellular organelles and suggest that dysregulation of MEF2 plays essential roles in the pathogenesis of PD. Many kinases associated with transcription, translation, protein misfolding, autophagy, and cellular energy homeostasis are involved in the neurodegenerative process. Following the first demonstration that mitogen-activated protein kinase p38 (p38 MAPK) directly phosphorylates and activates MEF2 to promote neuronal survival, several other kinase regulators of MEF2s have been identified. These include protein kinase A and extracellular signal regulated kinase 5 as positive MEF2 regulators, and cyclin-dependent kinase 5 (Cdk5) and glycogen synthase kinase 3β as negative regulators in response to diverse toxic signals relevant to PD. It is clear that MEF2 has emerged as a key point where survival and death signals converge to exert their regulatory effects, and dysregulation of MEF2 function in multiple subcellular organelles may underlie PD pathogenesis. Moreover, several other kinases such as leucine-rich repeat kinase 2 and PTEN-induced putative kinase 1 (PINK1) are of particular interest due to their potential interaction with MEF2.

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Comprehensive mutational analysis of LRRK2 reveals variants supporting association with autosomal dominant Parkinson's disease

Cited by 11 publications

References 47 publications

VPS35 mutation in Japanese patients with typical Parkinson's disease

VPS35 mutation in Japanese patients with typical Parkinson's disease

LRRK2 GTPase dysfunction in the pathogenesis of Parkinson's disease

Modulation of Neuronal Survival Factor MEF2 by Kinases in Parkinson’s Disease

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