HARP syndrome is allelic with pantothenate kinase–associated neurodegeneration

Ching, Katherine H. L.; Westaway, S. K.; Gitschier, Jane; Higgins, J. J.; Hayflick, SJ

doi:10.1212/wnl.58.11.1673

Cited by 88 publications

(30 citation statements)

References 6 publications

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“…To date, 77 types of PANK2 mutations have been reported as being responsible for PKAN, including 47 types of missense mutations, nine types of nonsense mutations, 13 frameshift mutations, six mutations causing aberrant splicing, and two mutations causing an amino acid deletion [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. In an extensive study on correlations between HSS phenotype and genotype in which an early-onset rapidly progressive childhood type was classified as a classic form, and other types of HSS were classified as an atypical form, it was shown that all patients with classic HSS and one third of those with atypical HSS had PANK2 mutations [5].…”

Section: Discussionmentioning

confidence: 99%

“…Retinitis pigmentosa, optic atrophy, and intellectual retardation or decline are also common in the earlyonset childhood type [1,3]. After mutations in the pantothenate kinase 2 (PANK2) gene were found to be responsible for HSS [4], several studies revealed significant correlations between clinical phenotypes and types of PANK2 mutations [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Among those studies, only four reports have described the detailed clinical features of the adult-onset slowly progressive type of PKAN with PANK2 mutations [13,14,17,18].…”

Section: Introductionmentioning

confidence: 99%

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Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: Clinical features and 99mTc-ECD brain perfusion SPECT findings

Doi

Koyano

Miyatake

et al. 2010

Journal of the Neurological Sciences

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: Clinical features and 99mTc-ECD brain perfusion SPECT findings

Doi

Koyano

Miyatake

et al. 2010

Journal of the Neurological Sciences

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“…The recent identification of pantothenate kinase 2 (PANK2) gene mutations in NBIA as well as HARP syndrome represents a unique opportunity to better understand the pathogenesis of this neurodegenerative disease (Zhou et al, 2001;Ching et al, 2002;Houlden et al, 2003). PANK2 is a member of a family of eukaryotic genes encoding pantothenate kinases, which catalyze the phosphorylation of pantothenate (vitamin B5) to yield phosphopantothenate.…”

Section: Introductionmentioning

confidence: 99%

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

Kotzbauer¹,

Truax²,

Trojanowski³

et al. 2005

J. Neurosci.

136

126

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Mutations in the pantothenate kinase 2 (PANK2) gene have been identified in patients with neurodegeneration with brain iron accumulation (NBIA; formerly Hallervorden-Spatz disease). However, the mechanisms by which these mutations cause neurodegeneration are unclear, especially given the existence of multiple pantothenate kinase genes in humans and multiple PanK2 transcripts with potentially different subcellular localizations. We demonstrate that PanK2 protein is localized to mitochondria of neurons in human brain, distinguishing it from other pantothenate kinases that do not possess mitochondrial-targeting sequences. PanK2 protein translated from the most 5Ј start site is sequentially cleaved at two sites by the mitochondrial processing peptidase, generating a long-lived 48 kDa mature protein identical to that found in human brain extracts. The mature protein catalyzes the initial step in coenzyme A (CoA) synthesis but displays feedback inhibition in response to species of acyl CoA rather than CoA itself. Some, but not all disease-associated point mutations result in significantly reduced catalytic activity. The most common mutation, G521R, results in marked instability of the intermediate PanK2 isoform and reduced production of the mature isoform. These results suggest that NBIA is caused by altered neuronal mitochondrial lipid metabolism caused by mutations disrupting PanK2 protein levels and catalytic activity.

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“…The human PANK2 gene also encodes two protein isoforms, one of which preferentially localizes to mitochondria (11). Mutations in the human PANK2 coding sequence create a metabolic imbalance leading to either HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, pallidal degeneration) syndrome (12) or a progressive childhood neuropathy called PanK-associated neurodegeneration (PKAN) (10) characterized by iron accumulation in the basal ganglia. The human genetic data suggest that dysfunctional CoA biosynthesis due either to defective expression or to sequence alteration of a single PanK isoform can selectively impact the function of specific tissues.…”

mentioning

confidence: 99%

PPARα controls the intracellular coenzyme A concentration via regulation of PANK1α gene expression

Ramaswamy

Karim

Murti

et al. 2004

Journal of Lipid Research

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Pantothenate kinase (PanK) is thought to catalyze the first rate-limiting step in CoA biosynthesis. The fulllength cDNA encoding the human PanK1 ␣ protein was isolated, and the complete human PANK1 gene structure was determined. Bezafibrate (BF), a hypolipidemic drug and a peroxisome proliferator activator receptor-␣ (PPAR ␣ ) agonist, specifically increased hPANK1 ␣ mRNA expression in human hepatoblastoma (HepG2) cells as a function of time and dose of the drug, compared with hPANK1 ␤ , hPANK2 , and hPANK3 , which did not significantly increase. Four putative PPAR ␣ response elements were identified in the PANKI ␣ promoter, and BF stimulated hPANK1 ␣ promoter activity but did not alter the mRNA half-life. Pantothenate (Pan) is a B complex vitamin (B 5 ) and is a nutritional requirement in mammals. Pan is the precursor for the biosynthesis of CoA, the predominant acyl group carrier in cells. Acyl moieties are attached to the terminal sulfhydryl of CoA, and these compounds participate in over 100 different reactions in intermediary metabolism (1-4). Short-chain CoA thioesters, such as acetyl-CoA or succinyl-CoA, are the most abundant components of the CoA pool (5) and are important intermediates in the tricarboxylic acid cycle, which coordinates carbon utilization and oxidative energy production. CoA is also an essential cofactor in long-chain fatty acid metabolism. CoA transfers fatty acids to and from the mitochondrial carnitine transferases and carries all of the intermediates of fatty acid ␤ -oxidation in peroxisomes and mitochondria. CoA acyl-thioesters are also the substrates for the acyltransferases and desaturases involved in membrane phospholipid formation, triglyceride synthesis, and protein acylation. Thus, CoA participates in the major anabolic and catabolic pathways critical to cell growth and function.Pan is phosphorylated by pantothenate kinase (PanK) to yield 4 Ј -phosphopantothenate (P-Pan) in the first enzymatic reaction leading to CoA. PanK activity controls the cellular level of CoA in bacteria (6) and mammals (7,8), and there are multiple Pank genes that are differentially expressed and regulated in mammalian tissues (4, 9-11). The first mammalian gene identified was the mouse Pank1 gene, which encodes two proteins that differ at the N terminus due to alternative splicing of distinct initiating exons (9). PanK1 ␣ enzyme activity is feedback inhibited by both unacylated CoA and acetyl-CoA (9), whereas the PanK1 ␤ isoform is less sensitive to feedback regulation by acetyl-CoA and is stimulated by unacylated CoA (8). The human PANK2 gene also encodes two protein isoforms, Abbreviations: BF, bezafibrate; HSS, Hallervorden-Spatz syndrome; P-Pan, 4 Ј -phosphopantothenate; P-PanSH, 4 Ј -phosphopantetheine; Pan, pantothenate; PanK, pantothenate kinase; PKAN, pantothenate kinase-associated neurodegeneration; PPAR ␣ , peroxisome proliferator activator receptor-␣ ; RACE, rapid amplification of cDNA ends.

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HARP syndrome is allelic with pantothenate kinase–associated neurodegeneration

Cited by 88 publications

References 6 publications

Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: Clinical features and 99mTc-ECD brain perfusion SPECT findings

Siblings with the adult-onset slowly progressive type of pantothenate kinase-associated neurodegeneration and a novel mutation, Ile346Ser, in PANK2: Clinical features and 99mTc-ECD brain perfusion SPECT findings

Altered Neuronal Mitochondrial Coenzyme A Synthesis in Neurodegeneration with Brain Iron Accumulation Caused by Abnormal Processing, Stability, and Catalytic Activity of Mutant Pantothenate Kinase 2

PPARα controls the intracellular coenzyme A concentration via regulation of PANK1α gene expression

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