2011
DOI: 10.1002/humu.21527
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Pathogenic effects of novel mutations in the P‐type ATPase ATP13A2 ( PARK9 ) causing Kufor‐Rakeb syndrome, a form of early‐onset parkinsonism

Abstract: Kufor-Rakeb syndrome (KRS) is a rare form of autosomal recessive juvenile or early-onset, levodopa responsive parkinsonism and has been associated with mutations in ATP13A2(also known as PARK9), a lysosomal type 5 P-type ATPase. Recently, we identified novel compound heterozygous mutations, c.3176T>G (p.L1059R) and c.3253delC (p.L1085WfsX1088) in ATP13A2 of two siblings affected with KRS. When overexpressed, wild-type ATP13A2 localized to Lysotracker-positive and LAMP2-positive lysosomes while both truncating … Show more

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Cited by 109 publications
(87 citation statements)
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References 33 publications
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“…[102][103][104] Subjects normally display generalized brain atrophy with evidence of diminished nigrostriatal dopaminergic function consistent with the observation that ATP13A2 is particularly enriched in the substantia nigra. 103,105,106 Mutations of ATP13A2 results in its re-localization from intracellular acidic vesicular compartments to the endoplasmic reticulum in mammalian cells where it is subsequently digested via the proteasomal ERassociated degradation pathway.…”
Section: Atp13a2supporting
confidence: 58%
“…[102][103][104] Subjects normally display generalized brain atrophy with evidence of diminished nigrostriatal dopaminergic function consistent with the observation that ATP13A2 is particularly enriched in the substantia nigra. 103,105,106 Mutations of ATP13A2 results in its re-localization from intracellular acidic vesicular compartments to the endoplasmic reticulum in mammalian cells where it is subsequently digested via the proteasomal ERassociated degradation pathway.…”
Section: Atp13a2supporting
confidence: 58%
“…Genetic studies have also implicated other lysosomal-associated genes with sporadic PD. A loss-of-function mutation in the lysosomal cation-transporting ATPase, Adenosine-3-phosphate 13A2 (ATP13A2) will result in abnormal lysosomal acidification in Kufor-Rakeb syndrome as well as some juvenile and young-onset forms of PD (Di Fonzo et al, 2007;Park et al, 2011;Ramirez et al, 2006). Mutations in the lysosomal proton transporting ATPase, ATP6AP2 causes X-linked parkinsonism with spasticity (Korvatska et al, 2013), and a mutation in VPS35, an endosomal-lysosomal trafficking gene, causes autosomal dominant forms of PD (Vilarino-Guell et al, 2011;Zimprich et al, 2011).…”
Section: Discussionmentioning
confidence: 99%
“…Genetic studies have enabled the identification of 18 gene loci, named PARK1-18, that result in autosomally dominant or recessive inherited forms of PD or are associated with an increased risk for developing PD (2). Among these, the ATP13A2 gene (PARK9) has been linked to autosomal recessive, levodopa-responsive, nigrostriatal-pallidalpyramidal neurodegeneration (Kufor-Rakeb syndrome) as well as to some juvenile and young-onset forms of PD (3)(4)(5)(6)(7). The PARK9 gene encodes the protein ATP13A2, a transmembrane lysosomal type 5 P-type ATPase protein consisting of 1,180 amino acid residues (4).…”
mentioning
confidence: 99%
“…Missense or truncation mutations in ATP13A2 are pathogenic by causing loss of function. For example, cells expressing ATP13A2 mutations exhibit retention of ATP13A2 in the endoplasmic reticulum (ER) and predispose cells to ER stress-induced cell death followed by degradation by means of the ER-associated degradation-proteasomal pathway (6,10). Putative lysosomal dysfunction through loss of ATP13A2 function might lead to insufficient lysosomal protein degradation.…”
mentioning
confidence: 99%