Peroxisomal Biogenesis Disorder

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  • Peroxisomal biogenesis disorders generally affect approximately 1 in 50,000 infants, and approximately 9-16% of cases are attributed to mutations in PEX6.(More...)
  • We selected pex16 and pex2 because both are conserved PBD disease gene homologs that act in distinct steps of peroxisomal biogenesis ( Fig 1 ) ensuring that our results will uncover key, cell biological aspects of peroxisomes rather than gene specific ones.(More...)
  • An infantile form of Refsum disease also exists and is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including elevated plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids.(More...)

POSSIBLY USEFUL

  • The Global Foundation for Peroxisomal Disorders is a resource for families who have received a diagnosis of Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), D-bifunctional protein deficiency and rhizomelic chondrodysplasia punctata (RCDP) through connections to medical professionals, scientific professionals, and family support networks.(More...)

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Peroxisomal Biogenesis Disorder
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Peroxisomal biogenesis disorders generally affect approximately 1 in 50,000 infants, and approximately 9-16% of cases are attributed to mutations in PEX6. [1] In Japan, the incidence of all peroxisomal biogenesis disorders may be lower than 1 in 500,000. [1]

Peroxisomal biogenesis disorder results from defects in the genes that form the peroxisomes, essential micro-machines inside the cell that are involved in breaking down and producing certain lipids. [2] Peroxisomal biogenesis disorders are caused by defective assembly of the organelle resulting in some amount of deficient functional peroxisomes. [3] Peroxisomal disorders can be categorized into 2 major groups based on the function that is disrupted: peroxisomal biogenesis disorders and single peroxisomal enzyme deficiencies. [3] Courtesy of Samathana Jolicoeur Gideon Jolicoeur, now 4 1/2, has a rare genetic disease called Peroxisomal Biogenesis Disorder that caused him to be born blind and deaf and with limited cognitive abilities and a short lifespan. [4] After months of uncertainty, a neurologist ran a specific blood test that confirmed his worst fears: Gideon had a rare degenerative condition called Peroxisomal Biogenesis Disorder. [4] Chen H, Liu Z, Huang X. Drosophila models of peroxisomal biogenesis disorder: peroxins are required for spermatogenesis and very-long-chain fatty acid metabolism. [5] Date: June 22, 2017 Source: Baylor College of Medicine Summary: Peroxisomal biogenesis disorder, which has been linked only to lipid metabolism, is also associated with sugar metabolism. [2] The condition, also known as peroxisomal biogenesis disorder, had been linked only to lipid or fat metabolism. [2] Peroxisomal biogenesis disorder: New link to sugar metabolism. [2] Peroxisomal biogenesis disorders include the Zellweger spectrum: Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease. [3] It can also be referred to as Peroxisomal Biogenesis Disorders, Zellweger Syndrome Spectrum, NALD, Cerebrohepatorenal Syndrome, and ZSS. It can affect many body organs, including the kidneys, eyes, and hearing. [6] Zellweger syndrome is an autosomal-recessive inherited peroxisomal biogenesis disorder. [7] Raas-Rothschild A, Wanders RJ, Mooijer PA, Gootjes J, Waterham HR, Gutman A, et al. A PEX6-defective peroxisomal biogenesis disorder with severe phenotype in an infant, versus mild phenotype resembling Usher syndrome in the affected parents. [8] Common Peroxisomal Biogenesis Disorder symptoms include bone loss, kidney and liver dysfunction, deafblindness, seizures and dental and blood issues. [9] They were honest with their daughter, Laynie, now 7, early on that she may not have her little brother for long, but she became an expert in Peroxisomal Biogenesis Disorder. [4]

Analyses of biochemical markers for peroxisomal disease suggested a mild peroxisomal defect and functional studies in fibroblasts confirmed the existence of a peroxisome biogenesis disorder. [8] "Peroxisomal biogenesis disorder: New link to sugar metabolism." [2] The presence of these ghosts with PMPs is explained by the fact that the signals and machineries involved in peroxisomal matrix and membrane protein import are different, and most (but not all) of these biogenesis disorders affect only matrix protein import. [7] Peroxisomal disorders are divided into two groups: (1) peroxisome biogenesis disorders (PBDs), and (2) single peroxisomal enzyme defects. [8] Wanders RJ, Waterham HR. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. [5]

Every cell in the human body has peroxisomals, so the disorders affect every part of the body, said Katie Sarca of Myrtle Beach, whose son, T.J., has Peroxisomal Biogenesis Disorder-Zellweger Spectrum Disorder. [9] T.J. Sarca, who suffers from Peroxisomal Biogenesis Disorder-Zellweger Spectrum Disorder, walks around the track at St. James High School. [9]

Most proteins destined for the peroxisomal matrix depend on the peroxisomal targeting signals (PTSs), which require the PTS receptor PEX5, whose deficiency causes fatal human peroxisomal biogenesis disorders (PBDs). [10] Peroxisomal diseases fall into two categories: single-enzyme defects and peroxisomal biogenesis disorders (PBDs; Waterham et al., 2016 ). [10] The GFPD was founded on October 5th, 2010 by a small but dedicated group of parents of children affected by peroxisomal biogenesis disorder. [11] Duranti G, Boenzi S, Rizzo C, et al. Urine acylcarnitine analysis by ESI-MS/MS: a new tool for the diagnosis of peroxisomal biogenesis disorders. [12] At 7 months old, he was diagnosed with something called Peroxisomal Biogenesis Disorder which (among other complications) has left him legally blind and severe-to-profoundly deaf. [13]

We selected pex16 and pex2 because both are conserved PBD disease gene homologs that act in distinct steps of peroxisomal biogenesis ( Fig 1 ) ensuring that our results will uncover key, cell biological aspects of peroxisomes rather than gene specific ones. [5] Our work suggests that delineating these gene regulatory programs, and how they are altered in PBD is important to our understanding of how defective peroxisomal biogenesis impacts human health. [5] To perform detailed phenotypic and biochemical analysis and identify new pathways that may be affected when peroxisomal function is lost, we studied two genes required for Drosophila peroxisomal biogenesis. [5] More importantly, we found that Drosophila peroxisomal biogenesis mutants have global reductions in glycolytic intermediates and glycogen with abnormalities in the pentose phosphate pathway. [5] Therefore these genetic tools permit comparison of pex2 and pex16 mutants, two mutants that represent defects in different steps of the peroxisomal biogenesis pathway ( Fig 1C ). [5] We used fruitfly ( Drosophila melanogaster) to study the metabolism and genetics of peroxisomal biogenesis to gain insight into the disease process. [5] We identified co-regulation of peroxisomal genes and carbohydrate metabolic genes along with a carbohydrate dependence phenotype in peroxisomal biogenesis mutants with metabolomic studies in Drosophila. [5] Consistent with a shared peroxisomal biogenesis phenotype in Drosophila, metabolomic studies of pex2 and pex16 mutants revealed numerous shared metabolic abnormalities that are due to global peroxisomal dysfunction in Drosophila. [5]

Genetic tools for studies of peroxisomal biogenesis in Drosophila. [5] Several recent studies have also explored peroxisomal biogenesis in Drosophila demonstrating the evolutionary conservation. [5] Citation: Wangler MF, Chao Y-H, Bayat V, Giagtzoglou N, Shinde AB, Putluri N, et al. (2017) Peroxisomal biogenesis is genetically and biochemically linked to carbohydrate metabolism in Drosophila and mouse. [5] These data suggest evolutionary conservation of the link between carbohydrate metabolism and peroxisomal biogenesis genes. [5] GFP-SKL produces a GFP with PTS1 targeting signal for the peroxisomal biogenesis machinery encoded by the pex genes necessary to import the protein into the peroxisomal matrix. [5] This would lead to the prediction of altered citric acid cycle metabolites in peroxisomal biogenesis mutants. [5] To determine which pathways were enriched for altered metabolites in peroxisomal biogenesis mutants we performed a Metabolite Set Enrichment Analysis (MSEA). [5] A comprehensive metabolic profile of peroxisomal biogenesis mutants is lacking. [5] "We are continuing our investigations and hope they will lead us to better understand how sugar metabolism is linked to peroxisomal biogenesis disorders." [2] There are several possible explanations for how peroxisomal biogenesis mutations can perturb carbohydrate metabolism. [5] S1 Fig. Genomic rescue strains for peroxisomal biogenesis factors pex2 and pex16. [5] Scale bar 10 ?m. (DAPI is shown in the composite) (C) The conserved peroxisomal biogenesis machinery is shown in schematic. [5]

The human peroxisomal disorders are now divided into two major categories: the disorders of peroxisome biogenesis, in which the organelle fails to form normally, and those disorders in which a single peroxisomal enzyme is deficient. [7] Peroxisome biogenesis disorders (PBD) are a group of multi-system human diseases due to mutations in the PEX genes that are responsible for peroxisome assembly and function. [5] Human diseases due to autosomal recessive loss of function mutations in the PEX genes comprise a group of severe disorders known as peroxisome biogenesis disorders (PBD) with involvement of brain, bone, kidney and liver and death within the first year of life. [5]

Peroxisome biogenesis disorders (PBD) are a group of rare diseases in which patients have genetic defects in the synthesis of peroxisomes. [5] Peroxisome biogenesis disorders (PBDs) are a group of autosomal recessive conditions caused by mutations in PEX proteins. [7] Ebberink MS, Csanyi B, Chong WK, Denis S, Sharp P, Mooijer PA, et al. Identification of an unusual variant peroxisome biogenesis disorder caused by mutations in the PEX16 gene. [8] The peroxisome biogenesis disorders, which are caused by mutations in any of 13 different PEX genes, include the Zellweger spectrum disorders. [8] Mast FD, Li J, Virk MK, Hughes SC, Simmonds AJ, Rachubinski RA. A Drosophila model for the Zellweger spectrum of peroxisome biogenesis disorders. [5] Gould SJ, Valle D. Peroxisome biogenesis disorders: genetics and cell biology. [5] Waterham, HR, Ebberink MS: Genetics and molecular basis of human peroxisome biogenesis disorders. [3] Peroxisomes are assumed to play a crucial role in the formation of cortex, cerebellum, and the inferior olivary nucleus because there are severe morphogenic defects in these tissues in peroxisome biogenesis disorders. [7] Peroxisome Biogenesis Disorder is one of countless diseases, disorders and life events that limit children's ability to sense and navigate the world around them. [14] Cody is a fearless and sensitive 7-year-old boy diagnosed with a Peroxisome Biogenesis Disorder (PBD). [14] Poll-The BT, Gootjes J, Duran M, De Klerk JB, Wenniger-Prick LJ, Admiraal RJ, et al. Peroxisome biogenesis disorders with prolonged survival: phenotypic expression in a cohort of 31 patients. [8] Warren DS, Wolfe BD, Gould SJ. Phenotype-genotype relationships in PEX10-deficient peroxisome biogenesis disorder patients. [8] Whereas peroxisomes are abundant in normal hepatocytes and fibroblasts, their numbers are drastically decreased in peroxisome biogenesis disorders. [7] Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW. Peroxisome biogenesis disorders. [5] Braverman NE, D'Agostino MD, Maclean GE. Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. [8]

An infantile form of Refsum disease also exists and is an autosomal recessive disorder of peroxisomal biogenesis, leading to many biochemical abnormalities, including elevated plasma concentration of phytanic acid, pristanic acid, very long chain fatty acids, and C27 bile acids. [12] Peroxisomal biogenesis disorder-Zellweger spectrum disorder is indeed rare — only about 80 children are born with it in the U.S. every year. [15]

Whereas RCDP1 is a peroxisomal biogenesis disorder (PBD), RCDP2 is classified as a single peroxisome enzyme deficiency ( Waterham and Ebberink, 2012 ). [16]

Because PEX2 has been implicated in peroxisome biogenesis ( Gootjes et al., 2004 ), and peroxisome biogenesis disorders (PBDs) are typically associated with impaired lipid metabolism and CNS myelin defects ( Krause et al., 2006 ), this prompted us to further explore a potential link between LRP1 and peroxisomes. [17] Defects in PEX genes can cause peroxisome biogenesis disorder (PBD), characterized by a broad range of symptoms, including aberrant brain development, white matter abnormalities, and neurodegeneration ( Berger et al., 2016 ). [17] Zellweger syndrome (ZWS) is a disorder that is a member of a family of disorders that result from defects in the biogenesis and/or functioning of the peroxisomes and are referred to as peroxisome biogenesis disorders, PBDs. [18] Peroxisome Biogenesis Disorders (PBD) are a rare group of genetic disorders in which an individual cannot properly produce peroxisomes inside their cells. [19] May 24, 2010, was the day I learned that my sweet Ginny had a peroxisome biogenesis disorder (PBD), a rare, genetic and terminal condition. [20]

Mutations in the PTS1 receptor gene, PXR1, define complementation group 2 of the peroxisome biogenesis disorders. [10] The peroxisome biogenesis disorder group 4 gene, PXAAA1, encodes a cytoplasmic ATPase required for stability of the PTS1 receptor. [10]

Refsum disease can be classified as a peroxisome biogenesis disorder. [12] Braverman NE, D'Agostino MD, Maclean GE. Peroxisome biogenesis disorders: Biological, clinical and pathophysiological perspectives. [12]

Peroxisomal biogenesis involves the assembly of peroxisomal membrane proteins (PMPs), followed by the import of matrix proteins ( Ma et al., 2011 ). [10] Earlier work in yeast, together with genetic phenotype complementation of peroxisome-deficient CHO mutant cells or human patient fibroblasts, identified PEX genes (encoding peroxins) necessary for peroxisomal biogenesis ( Erdmann, 2016 ; Honsho et al., 2016 ). [10] Besides its functions in peroxisomal biogenesis, TRIM37 is also an E3 ligase for histone 2A and promotes breast cancer development ( Bhatnagar et al., 2014 ). [10] The "promyelinating" function of the PPAR agonist is not reflected in peroxisomal biogenesis and more likely a result of improved (peroxisome-independent) lipid metabolism. [17] Mechanistic studies revealed a decrease in peroxisomal biogenesis factor-2 and fewer peroxisomes in OL processes. [17]

These diseases are referred to as disorders of peroxisomal biogenesis. [21] Abby Simpson first learned about the Global Foundation for Peroxisomal Disorders (GFPD) from the parent of a child who had Peroxisome Biogenesis Disorder (PBD). [22] The Global Foundation for Peroxisomal Disorders was founded in 2010 by parents of children impacted by Peroxisome Biogenesis Disorder. [23] Wanders, R. J. A., Waterham, H. R. Peroxisomal disorders I: biochemistry and genetics of peroxisome biogenesis disorders. [16]

Waterham, H. R., Ebberink, M. S. Genetics and molecular basis of human peroxisome biogenesis disorders. [16] His group focuses on peroxisome biogenesis disorders (PBDs), which include Zellweger spectrum disorder (PBD-ZSD) and rhizomelic chondrodysplasia punctata (RCDP). [24] Braverman NE, Raymond GV, Rizzo WB, Moser AB, Wilkinson ME, Stone EM, Steinberg SJ, Wangler MF, Rush ET, Hacia J, Bose M. Peroxisome biogenesis disorders in the Zellweger spectrum: An overview of current diagnosis, clinical manifestations, and treatment guidelines. [24] Identification of novel mutations and sequence variation in the Zellweger syndrome spectrum of peroxisome biogenesis disorders. [24]

Because October is an anniversary month for GFPD, events have been scheduled for an annual #PauseForPBD (Peroxisome biogenesis disorders) awareness day. [23] This first symptom began a year of doctor's visits and testing that ultimately led to a rare diagnosis of Peroxisome Biogenesis Disorder at 18 months of age. [25] Stephen is supporting Claire House after the Wirral Hospice cared for a close family friend's son, Harvey Jones Lanagan, who died from Peroxisome Biogenesis disorder, aged just four. [26]

POSSIBLY USEFUL

The Global Foundation for Peroxisomal Disorders is a resource for families who have received a diagnosis of Zellweger syndrome, neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), D-bifunctional protein deficiency and rhizomelic chondrodysplasia punctata (RCDP) through connections to medical professionals, scientific professionals, and family support networks. [1] The peroxisome is a subcellular organelle whose importance in cellular metabolism was first recognized when the previously identified human disorders Zellweger syndrome, X-linked adrenoleukodystrophy (XALD), and Refsum disease were discovered to be examples of peroxisomal malfunction. [7] Van Veldhoven PP. Biochemistry and genetics of inherited disorders of peroxisomal fatty acid metabolism. [5] These disorders lead to global defects in peroxisomal function and result in severe brain, liver, bone and kidney disease. [5]

The discovery of a peroxisomal defect in a child with this syndrome emphasized that this pattern represents one end of a clinical spectrum that may result from at least 10 genetic defects in peroxisomal assembly or the function of the single matrix enzymes, including PEX1, on chromosome 7q ( 50 ). [7] Human patients lacking the multifunctional protein 2 (MFP2), a D-bifunctional protein with enoyl-CoA hydratase and 3-hydroxy-acyl-CoA dehydrogenase activities, necessary for peroxisomal ?-oxidation of bile acid intermediates and pristanic acid, were found to have neuronal migration defects. [7] Gootjes J, Schmohl F, Mooijer PA, Dekker C, Mandel H, Topcu M, et al. Identification of the molecular defect in patients with peroxisomal mosaicism using a novel method involving culturing of cells at 40 degrees C: implications for other inborn errors of metabolism. [8] A key question that has not been addressed by the previous fly studies is whether the phenotype due to loss of peroxisomes is determined by any pathways in metabolism beyond peroxisomal lipids. [5] "It's been well established that several lipid pathways are altered in this disease; these are known peroxisomal functions, but there has been very little focus on other parts of metabolism. [2] While the increases in VLCFA and loss of plasmalogens in peroxisomal metabolism are likely to be a significant part of the pathogenesis of PBD, other metabolic pathways are also likely to play a role. [5] Therefore, the untargeted metabolic profiling identified defects in a number of pathways already implicated in peroxisomal biochemistry. [5] While this is not supported by the current inventory of peroxisomal proteins in Drosophila, mechanisms such as read-through at stop codons can lead to peroxisomal localization of some metabolic enzymes in yeast. [5] Faust JE, Verma A, Peng C, McNew JA. An inventory of peroxisomal proteins and pathways in Drosophila melanogaster. [5]

In deficiency of peroxisomal D-bifunctional protein, the progressive neurodegenerative syndrome begins in childhood. [7] To investigate the peroxisomal phenotypes we examined the mutant larval salivary glands using the Pex3 antibody and a peroxisomally localized green fluorescent protein (GFP-SKL) ( Fig 1A? ). [5] Interestingly, for nearly every step of glycogen synthesis and glycolysis the gene encoding the enzyme is co-regulated with one or more of these peroxisomal transcriptional clusters ( Fig 8B ). [5] Culturing patient fibroblasts at 40 C for 2 weeks resulted in a complete absence of peroxisomal staining with catalase immunofluorescence microscopy analysis, indicating the lack of import-competent peroxisomes at this elevated temperature (Fig. 2 ). [8] Peroxisomal mosaicism, that is, a mixed population of fibroblasts with normal peroxisome numbers and reduced numbers of peroxisomes, was observed in our patient. [8] This case highlights the importance of performing biochemical, functional, and genetic peroxisomal screening in patients with clinical presentations milder than those usually observed in Zellweger spectrum disorders. [8] This report describes a new missense mutation in PEX10 in a patient with mild clinical phenotype and highlights the importance of performing biochemical and genetic peroxisomal screening in patients with clinical presentations milder than those observed in ZSDs. [8]

When cultured at 37 C most cells revealed a normal peroxisomal staining, but in some cells a markedly reduced number of peroxisomes was observed. [8] Peroxisomes are subcellular organelles tasked with a discrete subset of metabolic reactions principally involving peroxisomal lipids. [5] Barry DS, O'Keeffe GW. Peroxisomes: the neuropathological consequences of peroxisomal dysfunction in the developing brain. [5]

Our data suggest that loss of either gene causes defective localization of peroxisomal markers and hence are likely to disrupt peroxisomal biogenesis/function. [5] Early peroxisomal proteins, pex3, pex19 and pex16 (purple diamond for pex16 and blue symbols) aid in designation of an ER-derived lipid bilayer (left). [5] Girzalsky W, Saffian D, Erdmann R. Peroxisomal protein translocation. [8] Platta HW, El Magraoui F, Baumer BE, Schlee D, Girzalsky W, Erdmann R. Pex2 and pex12 function as protein-ubiquitin ligases in peroxisomal protein import. [5] These studies suggest that additional or even distinct peroxisomal functions are involved in PBD pathogenesis. [5] To assess if peroxisomal function was altered in our mutants we examined canonical peroxisomal lipids using the same methods as employed for clinical diagnosis. [5] Moreover these mutants exhibit severe morphologic and functional peroxisomal defects. [5] These data demonstrate a particular sensitivity of peroxisomal mutants to glucose deprivation, suggesting that the metabolomics changes we observed in carbohydrate metabolism impact the physiology and behavior of peroxisomal mutant flies. [5] We hypothesized that this co-regulation in these key steps of carbohydrate metabolism might relate to the peroxisome's dependence on other pathways such as the citric acid cycle to metabolize the end products of peroxisomal catabolism. [5] Our metabolomics analysis also revealed new insights indicating that the use of untargeted metabolomics in peroxisomal studies could uncover unsuspected metabolic pathways involved in peroxisomal biochemistry. [5] The examination of biochemical pathways verified several known peroxisomal pathways ( Fig 5 ). [5]

Poulos A, Sharp P, Fellenberg AJ, Johnson DW. Accumulation of pristanic acid (2, 6, 10, 14 tetramethylpentadecanoic acid) in the plasma of patients with generalised peroxisomal dysfunction. [5] Three days after transfection there was restoration of PTS-1 protein import, confirming that PEX10 is responsible for the peroxisomal dysfunction in our patient (data not shown). [8] Patients with a milder clinical presentation often show less pronounced abnormalities of peroxisomal metabolites in body fluids and fibroblasts. [8]

Culturing fibroblasts at 40 C usually aggravates the defect, an effect that was also found in our study where a complete absence of peroxisomal staining with catalase immunofluorescence microscopy analysis was observed. [8] A more general alteration of peroxisomal lipids have been proposed as a developmental insult to the brain in PBD. [5] Our functional analysis of the peroxisomal lipids allowed a more comprehensive study of VLCFA metabolites in different stages of development. [5] Because of the abnormal VLCFA and phytanic and pristanic acid levels further peroxisomal studies in fibroblasts were performed. [8] Schluter A, Fourcade S, Domenech-Estevez E, Gabaldon T, Huerta-Cepas J, Berthommier G, et al. PeroxisomeDB: a database for the peroxisomal proteome, functional genomics and disease. [5] Peroxisomal biology is highly conserved across eukaryotes which has allowed this same genetic machinery to be studied across several model organisms. [5] The accumulation of VLCFAs as a result of peroxisomal ? -oxidation deficiency, depletion of plasmalogens, or reduced content of the polyunsaturated fatty acid docosahexaenoic acid (DHA) play a major role in impairment of neuronal migration. [7] The peroxisomal mutant flies exhibit a dramatic reduction in the level suggesting plasmalogen loss. [5] Given these changes we sought to test whether the peroxisomal mutants would be sensitive to reduced glucose intake. [5]

Definite diagnosis requires evaluation of peroxisomal functions. [6]

While a role for lipid metabolism in peroxisomal disorders is well established, carbohydrate metabolism is thought to be a more central energy-producing process utilizing cytosolic and mitochondrial enzymes crucial for energy production and is not generally implicated in PBD. We have uncovered a previously unappreciated metabolic, phenotypic and gene-expression link between peroxisomes and carbohydrate metabolism. [5] The most common peroxisomal disorder, X-linked adrenoleukodystrophy, is an enzyme deficiency due to mutations in the ABCD1 gene. [3]

Zellweger syndrome, neonatal adrenoleukodystrophy, and infantile Refsum disease form the "Zellweger spectrum" and are clinically distinct from rhizomelic chondrodysplasia punctata due to PEX7 gene mutations. 178, 179 These disorders are characterized by developmental delay, hypotonia, neurosensory deafness, optic atrophy, and dysmorphic facial development. [7] Known as cerebrohepatorenal syndrome, Zellweger syndrome is a disorder of peroxisome biogenesis that lies at the severe end of a clinical spectrum that includes neonatal adrenoleukodystrophy and infantile Refsum disease. [7] This chapter provides a description of the disorders of peroxisome biogenesis, XALD, and Refsum disease, and concludes with a brief description of the remaining single-enzyme disorders. [7]

The PBD group comprises four different autosomal recessive disorders: Zellweger syndrome (ZS), neonatal adrenoleukodystrophy (NALD), infantile Refsum disease (IRD), and rhizomelic chondrodysplasia punctata (RCDP) type 1 ( Aubourg et al., 1985; Steinberg et al., 2006 ). [7]

The differential diagnosis of acute SMA type I comprises the whole spectrum of the floppy infant syndrome, including cerebral malformations, perinatal asphyxia, metabolic defects, Prader-Willi syndrome, Zellweger's syndrome, mitochondrial disease, and other congenital neuromuscular disorders. [7] "Studying this rare disease can help us understand peroxisomes better, and, in turn, that knowledge will help clarify the role of peroxisomes in Alzheimer's and other disorders. [2]

Warren DS, Morrell JC, Moser HW, Valle D, Gould SJ. Identification of PEX10, the gene defective in complementation group 7 of the peroxisome-biogenesis disorders. [8] Any mutation involving the genes that create or work the peroxisomes can lead to the development of any of the Zellweger Spectrum Disorders. [6] We report a case of a patient with Zellweger spectrum disorder due to a novel mutation in the PEX10 gene, presenting with a mild late-onset neurological phenotype. [8] Mignarri A, Vinciguerra C, Giorgio A, Ferdinandusse S, Waterham H, Wanders R, et al. Zellweger spectrum disorder with mild phenotype caused by PEX2 gene mutations. [8]

Zellweger spectrum disorders are a group of rare disorders that create the same disease process. [6] Zellweger spectrum disorders are a group of autosomal recessive genetic disorders. [6]

Before they were told that a rare genetic disorder would claim their infant son, Gideon, by his first birthday, Samantha and Kevin Jolicoeur struggled for answers. [4] Both Sarca and Gamble they hope the event and the work of the foundation helps get the word out about these rare disorders. [9]

Lagerstedt SA, Hinrichs DR, Batt SM, Magera MJ, Rinaldo P, McConnell JP. Quantitative determination of plasma c8-c26 total fatty acids for the biochemical diagnosis of nutritional and metabolic disorders. [5] PBD is a degenerative disorder that results in the loss of hearing and sight. [14] It is dominated by sensory features and results both from a Schwann cell disorder and from axonal degeneration. [7] Everybody was thinking this was mainly a lipid disorder," Wangler said. [2]

Fidaleo M: Peroxisomes and peroxisomal disorders: the main facts. [3] Peroxisomes are present in nearly all tissues and most of the peroxisomal disorders have neurologic expression. [7] Moser AB, Rasmussen M, Naidu S, Watkins PA, McGuinness M, Hajra AK, et al. Phenotype of patients with peroxisomal disorders subdivided into sixteen complementation groups. [8] The absence of a mutation, therefore, does not eliminate the possibility of a peroxisomal disorder. [3] Wanders RJ. Metabolic and molecular basis of peroxisomal disorders: a review. [5] Wanders RJ, Waterham HR: Peroxisomal disorders: the single peroxisomal enzyme deficiencies. [3] Peroxisomal disorders are so rare and mystifying, even mothers of children who suffer from them have a hard time describing them. [9] Recommended first-tier biochemical testing for peroxisomal disorders analyzes very long chain fatty acids is POX / Fatty Acid Profile, Peroxisomal, Serum. [3] The panel targets coding exons of 21 genes described to be involved in peroxisomal disorders including the 13 PEX genes (+/- 25 bases, according to RefSeq database and assembly Feb. 2009 (GRCh37/hg19)). [8]

Peroxisomes are formed by the action of 14 peroxins encoded by PEX genes, the majority of which are involved in translocation of peroxisomal enzymes into the matrix, with others designating peroxisomal membrane. [5] Although diseased cells lack detectable peroxisomes when analyzed using antibodies to peroxisomal matrix markers, remnant membranous structures termed "ghosts? with peroxisomal membrane proteins (PMPs) are present. [7] Immunofluorescence microscopy analysis using antibodies raised against catalase, a peroxisomal matrix protein, did show abnormal peroxisomal staining but not in all cells. [8] In Drosophila, PTS1 is the only system that allows localization into the peroxisomal matrix as PTS2 proteins are not present. [5] Based on this pattern of similar co-regulation between peroxisomal genes and carbohydrate metabolism we hypothesized that there may be similarities between the carbohydrate metabolism defect we observed in Drosophila pex2 and pex16 mutants and those observed in the Pex5 liver conditional mouse. [5] The y-axis shows the enrichment score or Kolmogorov-Smirnov-like statistic representing to what degree genes are over-represented in the ranked list of genes across the murine genome. (C) Overlap of the Drosophila and mouse liver peroxisomal gene clusters. [5] Amongst the top 1000 genes from each gene cluster we selected genes that are 1) involved in glucose metabolism and 2) represented in the top 1000 of more than one peroxisomal gene cluster in both fly and mouse. [5] This selection identified 10 fly genes, corresponding to 12 mouse homologs in glucose metabolism that are strongly co-regulated with peroxisomal genes in both flies and mice. [5] We also find a strong transcriptional co-regulation between peroxisomal genes in the fly and enzymes in glucose metabolism, and show that similar transcriptional signatures are observed in mice. [5] Our work points to the importance of peroxisomal gene regulation in understanding not only peroxisomal biology but also in understanding PBD. We observed closely co-regulated groups of genes in flies and mice. [5]

Overall, the results observed in fibroblasts suggest that the mutated PEX10 protein can partly be correctly targeted to the peroxisomal membrane and has residual activity, which is in line with the biochemical and clinical presentation of our patient. [8] Fig. 2 Immunofluorescence microscopy analysis using antibodies raised against catalase, a peroxisomal matrix enzyme, in skin fibroblasts of a control subject ( left panels ) and the patient, F1453 ( right panels ) cultured at 37 C ( upper panels ) and 40 C ( lower panels ) for 2 weeks. [8] This approach revealed five distinct gene clusters containing peroxisomal genes in Drosophila ( Fig 8A ). [5] We undertook an analysis using the g:Profiler starting with a manually curated list of mouse peroxisomal genes which we analyzed informatically in liver transcriptional datasets in mouse ( S5 Fig, S7 Table ). [5] We first assembled a list of peroxisomal genes in the fly and examined their expression profile in existing databases to find genes whose expression correlates with the expression of these peroxisomal genes using g:Profiler tools ( Fig 8 ; S6 Table ). [5]

Taken together these results suggest extensive co-regulation of transcription between peroxisomal genes and carbohydrate metabolism genes in Drosophila. [5] Indeed key steps in carbohydrate metabolism were found to be strongly co-regulated with peroxisomal genes in flies and mice. [5] Therefore, in murine liver there is significant co-regulation of peroxisomal genes and genes involved in carbohydrate metabolism. [5] Gene network and metabolomic enrichment of carbohydrate metabolism in peroxisomal gene networks. [5]

The genes are all enriched in multiple peroxisomal gene clusters in fly and mouse. [5] Mouse liver peroxisomal gene clusters, mouse liver peroxisomal genes are grouped into 4 closely co-regulated clusters. [5] Overview of representation of PGC and AMPK regulated genes in peroxisomal gene clusters. [5]

These included unanticipated changes in metabolites in glycolysis, glycogen metabolism, and the pentose phosphate pathway, carbohydrate metabolic pathways that do not utilize known peroxisomal enzymes. [5] Our work adds to a growing realization that peroxisomal function is a process that interplays with other metabolic pathways, and suggests that PBD pathogenesis may extend into other metabolic pathways beyond peroxisomal enzymes. [5] Using metabolomics we uncovered defects in multiple biochemical pathways including defects outside the canonical specialized lipid pathways performed by peroxisomal enzymes. [5]

In mice, studies of a spectrum of enzymatic and biogenesis defects in global and conditional knockouts has allowed insight into the role of peroxisomes in vertebrate tissues. [5] Subramani S. Components involved in peroxisome import, biogenesis, proliferation, turnover, and movement. [5] Sardiello M, Palmieri M, di Ronza A, Medina DL, Valenza M, Gennarino VA, et al. A gene network regulating lysosomal biogenesis and function. [5] The importance of peroxisomes in metabolism is evident by the existence of a large group of genetic diseases associated with impaired peroxisome biogenesis and function. [8] Baes M, Van Veldhoven PP. Mouse models for peroxisome biogenesis defects and beta-oxidation enzyme deficiencies. [5] Maxwell M, Bjorkman J, Nguyen T, Sharp P, Finnie J, Paterson C, et al. Pex13 inactivation in the mouse disrupts peroxisome biogenesis and leads to a Zellweger syndrome phenotype. [5]

We studied pex2 and pex16 mutant flies in order to compare different biogenesis defects in the fly. [5] These PEX genes encode for proteins called peroxins that are involved in peroxisome biogenesis and/or protein import. [8] Fujiki Y, Okumoto K, Mukai S, Honsho M, Tamura S. Peroxisome biogenesis in mammalian cells. [5]

Hiebler S, Masuda T, Hacia JG, Moser AB, Faust PL, Liu A, et al. The Pex1-G844D mouse: a model for mild human Zellweger spectrum disorder. [5] "Zellweger spectrum disorders: clinical manifestations in patients surviving into adulthood". [6] Ebberink MS, Mooijer PA, Gootjes J, Koster J, Wanders RJ, Waterham HR. Genetic classification and mutational spectrum of more than 600 patients with a Zellweger syndrome spectrum disorder. [8]

PBDs include the Zellweger spectrum disorders (ZSDs) and rhizomelic chondrodysplasia punctata type 1 and 5. [8] Children with Zellweger Spectrum disorder can have hearing loss with onset during the first months following birth. [6]

Cytochemical evaluation shows mislocation of the peroxisomal matrix protein catalase to the cytosol. [8] Dammai V, Subramani S. The human peroxisomal targeting signal receptor, Pex5p, is translocated into the peroxisomal matrix and recycled to the cytosol. [5]

While pex16 is involved in early peroxisomal membrane formation, pex2 is a component of an ubiquitination complex that functions in matrix protein import. [5] Recent studies have identified that the activation of the mTORC1 pathway in response to ROS occurs on the peroxisomal membrane, a process dependent on ATM. [5] Complementation studies can be performed on fibroblasts to identify which peroxisomal gene is deficient. [7] We find that both flies and mice strongly co-regulate peroxisomal genes and carbohydrate metabolizing genes, and noticed that twelve vertebrate genes are co-regulated with the corresponding ten fly genes. [5] The y-axis shows the enrichment score or Kolmogorov-Smirnov-like statistic representing to what degree genes are over-represented in the ranked list of genes across the murine genome. (B) Gene set enrichment analysis (GSEA) of peroxisomal genes in mouse liver networks showing a strong enrichment for TCA cycle. [5]

Fatty alcohols appear to accumulate in pex mutant flies. (C) Purine catabolism relies on peroxisomal enzymes and purine metabolites are altered in the pex mutants. [5] Peroxisomal enzyme deficiencies cause a disruption in peroxisomal function, although the organelles remain intact. [3] Most cases are due to a deficiency in a peroxisomal enzyme, phytanoyl-CoA 2-hydroxylase (PAHX). [7] Ding J, Loizides-Mangold U, Rando G, Zoete V, Michielin O, Reddy JK, et al. The peroxisomal enzyme L-PBE is required to prevent the dietary toxicity of medium-chain fatty acids. [5]

PEX10, which has ubiquitin ligase activity, is required, together with PEX2 and PEX12, for the ubiquitination of PEX5 in the peroxisomal membrane. [8]

The ubiquitylation at this site on PEX5 is reversed in vitro by USP2. (B) TRIM37-mediated monoubiquitylation of PEX5 at K464 stabilizes PEX5 by inhibiting its proteasome-mediated turnover via the RADAR pathway, thereby enhancing import of peroxisomal proteins. [10] The results are representative of three independent experiments. (E) Subcellular distribution of peroxisomal proteins in HepG2 control, TRIM37 KD, and PEX5 KD cells. [10] TRIM37 depletion in cancer cell lines or mutation in a mulibrey nanism patient impairs the import of peroxisomal matrix proteins, but not of PMPs, indicating that this disease is a new PBD. Second, TRIM37 ubiquitylates PEX5 at K464, which promotes efficient PTS import. [10] These data show that TRIM37 depletion or mutation causes an import defect for peroxisomal matrix proteins, but not for PMPs, manifesting a similar phenotype as PEX5 depletion or mutation. [10] TRIM37 gene mutation causes a defect in the import of peroxisomal matrix proteins. (A) Diagram of TRIM37 structure and the fs mutation at Arg166. [10]

Immunostaining of endogenous TRIM37 confirmed its peroxisomal localization, showing colocalization with the PMP marker PMP70, although many dots containing TRIM37 were not peroxisomes ( Fig. 1 A ). [10] Refsum disease is a recessive disorder characterized by defective peroxisomal alpha-oxidation of phytanic acid. [12] Refsum disease, like other peroxisomal diseases, is a heterogeneous syndrome. [12]

Due to the lack of proper peroxisomal lipid metabolism very long-chain fatty acids and various branched-chain fatty acids accumulate in the tissues impairing their functions. [18] Increases in the ratios of C24/C22 and C26/C22 fatty acids is indicative of a defect in peroxisomal fatty acid metabolism. [18]

The latter depends on distinct peroxisomal targeting signals (PTSs): PTS1, comprising a noncleaved C-terminal tripeptide, SKL, or its conserved variants ( Gould et al., 1989 ); or PTS2, consisting of the nonapeptide sequence (R/K)(L/V/I/Q)XX(L/V/I/H/Q)(L/S/G/A/K)X(H/Q)(L/A/F) localized near the N terminus of the cargo protein ( Swinkels et al., 1991 ). [10] The initial step in the peroxisomal import of PTS1-containing cargoes is the recognition and binding of the PTS in the cytoplasm by the TPR domain of PEX5 (aa 296-580; Gatto et al., 2000 ). [10] Peroxisomal targeting signal-1 recognition by the TPR domains of human PEX5. [10]

The cDNAs encoding the PTS1-containing proteins (ACOX1, acyl-CoA oxidase 1; PECR, peroxisomal trans-2-enoyl-CoA reductase) were fused to the C terminus of GFP (GFP-ACOX1 and GFP-PECR). [10] We show that Lrp1 deficiency decreases production of peroxisomal proteins and disrupts cholesterol homeostasis. [17]

These results strongly indicate that the enhanced apoptosis caused by TRIM37 depletion depends, significantly but not completely, on PEX5-mediated peroxisomal protein import. [10] Ubiquitination of mammalian Pex5p, the peroxisomal import receptor. [10] Ubiquitination of the peroxisomal import receptor Pex5p is required for its recycling. [10] Dynamics of the peroxisomal import cycle of PpPex20p: Ubiquitin-dependent localization and regulation. [10] A conserved cysteine is essential for Pex4p-dependent ubiquitination of the peroxisomal import receptor Pex5p. [10]

How do we fix someone’s cells? We are hoping that it could help with peroxisomal disorders,” Marshall said. [15] A peroxisomal matrix protein import defect was also observed in HEK 293T cells depleted for TRIM37 (Fig. S1, D-F), suggesting the TRIM37 function in humans is cell type independent. [10] A similar peroxisomal matrix protein import defect was observed in another TRIM37 KD stable cell line (TRIM37 KD-2#) using a second shRNA (Fig. S1, G and H), excluding other off-target effects. [10] No defect was observed in localization of the PMPs PMP70 ( Fig. 2 B ) and PMP22-GFP ( Fig. 2, C and D ) upon TRIM37 depletion, indicating a role of TRIM37 only in peroxisomal matrix protein import. [10] TRIM37 ubiquitylates PEX5 by interacting with CT51 of PEX5, which is required for peroxisomal matrix protein import. (A) Diagram of PEX5 constructs and summary of their interactions with TRIM37. (B) TRIM37 and PEX5 (WT or the indicated mutants) were fused to the GAL4-BD and -AD, respectively, and transformed into the yeast AH109 strain. (C) HEK 293T cells were transfected with TRIM37-GFP together with the indicated myc-PEX5 mutants. [10] Overexpressing TRIM37 (Arg166fs)-GFP mutant protein in normal cells did not redistribute peroxisomal RFP-SKL (Fig. S2, D-F), excluding any dominant-negative effect of Arg166fs on peroxisomal matrix protein import. [10] Despite the almost complete depletion of TRIM37 in this cell line (Fig. S5 I), localization of both peroxisomal matrix and membrane proteins was normal in TRIM37 KD cells, as indicated by the distribution of GFP-PECR and PMP22-GFP, respectively (Fig. S5 J). [10] Bars: 10 m. (C and D) Localization of peroxisomal matrix and membrane proteins in HepG2 control and TRIM37 KD cells. [10] Loss of TRIM37 impairs import of peroxisomal matrix proteins. (A) TRIM37 detection in HepG2 control and TRIM37 KD cells. (B) Immunostaining of peroxisomal proteins in HepG2 control and TRIM37 KD cells. [10]

In developing OLs, Lrp1 deficiency leads to a decrease in peroxisomal gene products, most prominently a ~50% reduction in PEX2, an integral membrane protein that functions in the import of peroxisomal matrix proteins. [17] The di-aromatic pentapeptide repeats of the human peroxisome import receptor PEX5 are separate high affinity binding sites for the peroxisomal membrane protein PEX14. [10] PEX5, the shuttling import receptor for peroxisomal matrix proteins, is a redox-sensitive protein. [10] Our mechanistic studies deciphered an unexpected role of TRIM37 in PEX5 ubiquitylation: it maintains PEX5 stability and abundance, and hence increases PTS cargo imports into the peroxisomal matrix. [10] We identified a novel E3 ligase, TRIM37, mediating PEX5 stability and consequently affecting PTS protein import into the peroxisomal matrix ( Fig. 10 ). [10] We found that PEX5 is subject to enormous polyubiquitylation and degradation under oxidative stress (H 2 O 2 treatment), a condition that disfavors peroxisomal matrix protein import (Fig. S5, A-C; Apanasets et al., 2014 ). [10] Deficiency of PEX5 protein causes PBDs of CG2, manifesting peroxisomal matrix protein import defects ( Dodt et al., 1995 ; Wiemer et al., 1995 ). [10] Our results indicate that mulibrey nanism is a new type of PBD. TRIM37 is a PMP whose depletion or mutation causes a peroxisomal matrix protein import defect. [10]

The TRIM37 gene encodes a peroxisomal RING-B-box-coiled-coil protein: classification of mulibrey nanism as a new peroxisomal disorder. [10] Muscle-liver-brain-eye (mulibrey) nanism is a rare autosomal recessive growth disorder of prenatal onset caused by TRIM37 gene mutations ( Avela et al., 2000 ). [10] Mulibrey nanism is an autosomal recessive, prenatal onset growth disorder with characteristic dysmorphic features, cardiopathy, and hepatomegaly caused by TRIM37 gene mutation ( Avela et al., 2000 ; Karlberg et al., 2004 ). [10]

Although there are characteristic clinical features to Zellweger syndrome, this disorder is not due to defects in a single gene. [18] Classic Zellweger syndrome is a neonatal presenting severe disorder. [18]

What about families with another of the thousands of rare disorders? What about the public and convincing them that PBD and other rare diseases are important. [19] According to the organization, rare diseases are not that rare with at least 7,000 rare diseases and disorders affecting 30 million Americans with more than half of those affected being children. [15] Leys D, Petit H, Bonte-Adnet C, et al. Refsum's disease revealed by cardiac disorders. [12]

The importance of peroxisomes in the human nervous system is underscored by inherited disorders caused by complete or partial loss of peroxisome function, collectively described as Zellweger spectrum disorders ( Berger et al., 2016 ; Waterham et al., 2016 ). [17] Mutations in human PEX2 cause Zellweger spectrum disorder but have no apparent impact on white matter appearance ( Mignarri et al., 2012 ). [17]

Human peroxisomal targeting signal-1 receptor restores peroxisomal protein import in cells from patients with fatal peroxisomal disorders. [10] Human diseases caused by peroxisomal disorders highlight the necessity of this organelle. [10] Baldwin EJ, Harrington DJ, Sampson B, Feher MD, Wierzbicki AS. Safety of long-term restrictive diets for peroxisomal disorders: vitamin and trace element status of patients treated for Adult Refsum Disease. [12] Since 2010, we have grown our patient registry from 48 patients, to today serving over 400 families worldwide who have a living or deceased child with a peroxisomal disorder. [11] In our example, the Global Foundation for Peroxisomal Disorders (GFPD) started as a family email group (with 40 families) in the early days of the internet and grew to a nonprofit public charity in 2010 now serving over 400 families in 39 countries around the world. [19]

A single peroxisomal enzyme defect that causes deficiency of alpha-oxidation leads to accumulation of phytanic acid in blood and tissues of patients with Refsum disease. [12] Patients with Refsum disease are unable to degrade phytanic acid because of a deficient activity of phytanoyl-CoA hydroxylase (PhyH), a peroxisomal enzyme catalyzing the first step of phytanic acid alpha-oxidation. [12]

We found that TRIM37 localizes in peroxisomal membranes and ubiquitylates PEX5 at K464 by interacting with its C-terminal 51 amino acids (CT51), which is required for PTS protein import. [10] Therefore, TRIM37-mediated ubiquitylation stabilizes PEX5 and promotes peroxisomal matrix protein import, suggesting that mulibrey nanism is a new PBD. [10] This depletion of PEX5 impairs peroxisomal matrix protein import and enhances cell apoptosis. [10]

Subcellular fractionation also established that TRIM37 localized in the organelle fractions (P), similar to the peroxisomal matrix protein, catalase; the PMP PMP70; and other organelle proteins: LAMP1 (lysosome), VDAC1 (mitochondria), and Sec61-? (ER). [10] To dissect the subcellular localization of peroxisomal matrix and membrane proteins, the pellet fractions were extracted with either alkaline carbonate buffer (100 mM Na 2 CO 3 and 10 mM Tris-HCl, pH 11.5) or detergent buffer (2% Triton X-100 and 1 M NaCl) and incubated for 30 min on ice, followed by ultracentrifugation at 100,000 g for 40 min. Supernatants and pellets were collected. [10]

Peroxisome assembly: matrix and membrane protein biogenesis. [10] PPREs are found in genes important for lipid and glucose metabolism, and peroxisome biogenesis ( Fang et al., 2016 ; Hofer et al., 2017 ). [17] Collectively, our studies reveal a novel role for Lrp1 in peroxisome biogenesis, lipid homeostasis, and OPC differentiation during white matter development and repair. [17] Mechanistic studies uncover a novel role for Lrp1 in PPAR?-mediated OPC differentiation, peroxisome biogenesis, and CNS myelination. [17] Mechanistically, Lrp1 deficiency disrupts multiple signaling pathways implicated in OL differentiation, including AKT activation, cholesterol homeostasis, PPAR? signaling, peroxisome biogenesis and subcellular distribution. [17]

This suggests that defects in CNS myelinogenesis observed in Lrp1 cKO OL mice are likely not only a reflection of reduced peroxisome biogenesis or transport into internodes. [17] Proteins that are involved in and necessary for correct peroxisome biogenesis are called peroxins (PEX). [18] Zellweger syndrome represents the extreme of the clinical manifestation of peroxisome biogenesis dysfunction with patients rarely surviving their first year of life. [18]

Discovering regulators of centriole biogenesis through siRNA-based functional genomics in human cells. [10]

Peroxisomal matrix protein receptor ubiquitination and recycling. [10] Ubiquitination of the peroxisomal targeting signal type 1 receptor, Pex5p, suggests the presence of a quality control mechanism during peroxisomal matrix protein import. [10] PTS protein import occurs through the following steps: receptor-cargo binding in the cytoplasm; docking of the receptor-cargo complex at peroxisomal membranes and translocation to the matrix; and cargo release and recycling of receptors to the cytosol for the next round of import ( Ma et al., 2011 ). [10] In contrast to monoubiquitylation, polyubiquitylation targets yeast Pex5 for proteasomal degradation via the RADAR (receptor accumulation and degradation in the absence of recycling) pathway, a quality-control system preventing the accumulation of nonfunctional Pex5 on peroxisomal membranes ( Kiel et al., 2005 ). [10] Polyubiquitylation occurs at one or two lysine residues near the N terminus of PEX5 in yeast, which serves as a quality-control system (also called the RADAR pathway; Ln et al., 2006 ) that prevents accumulation of the nonfunctional PEX5 at the peroxisomal membrane ( Kiel et al., 2005 ). [10]

PBDs are more complex in etiology in that many peroxisomal enzymes are affected, generally via lack of peroxisomal protein import ( Waterham et al., 2016 ). [10]

Since Lrp1 ablation leads to (i) a reduction in peroxisomal gene products, (ii) altered PPAR? signaling and, (iii) dysregulation of cholesterol homeostasis, the combined effects of multiple metabolic defects is a likely cause for impaired OPC differentiation. [17] To address whether TRIM37 resides in the peroxisomal membrane or matrix, the organelle fractions were subjected to alkaline carbonate or Triton X-100 extraction, respectively. [10]

RANKED SELECTED SOURCES(26 source documents arranged by frequency of occurrence in the above report)

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2. (57) TRIM37, a novel E3 ligase for PEX5-mediated peroxisomal matrix protein import | JCB

3. (33) Identification of a novel mutation in PEX10 in a patient with attenuated Zellweger spectrum disorder: a case report | SpringerLink

4. (21) Zellweger syndrome - an overview | ScienceDirect Topics

5. (14) LRP1 regulates peroxisome biogenesis and cholesterol homeostasis in oligodendrocytes and is required for proper CNS myelin development and repair | eLife

6. (10) Refsum Disease: Background, Pathophysiology, Etiology

7. (10) PDP - Clinical: Peroxisomal Disorder Panel by Next-Generation Sequencing

8. (9) Peroxisomal biogenesis disorder: New link to sugar metabolism -- ScienceDaily

9. (7) Zellweger Syndrome

10. (7) Zellweger spectrum disorders - Wikipedia

11. (5) Parents advocate for kids with mysterious illness | News | southstrandnews.com

12. (4) Boy in 'raspberry' video outlives diagnosis, inspires others - TODAY.com

13. (3)

14. (3) PROJECT C.O.D.I. -- Not Impossible

15. (3) Peoria family promotes Rare Diseases Day for 7-year-old son - News - Journal Star - Peoria, IL

16. (3) OMIM Entry - # 222765 - RHIZOMELIC CHONDRODYSPLASIA PUNCTATA, TYPE 2; RCDP2

17. (3) On Rare Disease Day, Remember What Family Organizations Can Do - Wangler Lab

18. (3) Joseph Hacia | USC Profiles

19. (2) The Global Foundation for Peroxisomal Disorders - GuideStar Profile

20. (2) Jimmie Tramel: Too-short life of child results in support for others | Jimmietramel | tulsaworld.com

21. (1) "Before we got Gideons diagnosis, we. - Love What Matters

22. (1) Pause for PBD - Guest Blog - Web 2017 - Tulsa, OK

23. (1) Single enzyme defects of peroxisomal beta-oxidation

24. (1) Volunteer opportunity presents learning experience for SECD students | College of Education and Human Sciences

25. (1) Rare Disease Day 2019 - Story: A Life of Love by Ashley

26. (1) Peroxisome - definition of peroxisome by The Free Dictionary

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