There has been little or no research regarding many critically important aspects of Prader-Willi syndrome (PWS), which is terribly unfortunate because a better understanding of mitochondrial function, protein, fat and glucose metabolism, thyroid function, protein glycosylation, and many other aspects of PWS has significant potential for identifying new treatment strategies that could greatly help with the eating issues, cognitive and behavioral impairments, hypotonia, low energy, and other aspects of PWS. This page therefore discusses some of what I believe are critical areas for PWS research. It is very much a work-in-progress and is therefore a far from complete catalog of the many aspects of PWS that desperately need investigation if its treatment is to ever move forward.
Energy metabolism
Nuclear respiratory factor-1 (NRF1) and mitochondrial and metabolic function in PWS
The SNRPN 5-prime region colocalizes with the PWS imprinting center and contains 2 DNase I hypersensitive sites, DHS1 at the SNRPN promoter and DHS2 within intron 1, exclusively on the paternally inherited chromosome. ... Analysis of DHS1 by in vivo footprinting and chromatin immunoprecipitation identified allele-specific interactions with multiple regulatory proteins, including NRF1 (OMIM 600879), which regulates genes involved in mitochondrial and metabolic functions. DHS2 acted as an enhancer of the SNRPN promoter and contained a highly conserved region that showed allele-specific interactions with unphosphorylated RNA polymerase II (180660), YY1 (600013), Sp1 (189906), and NRF1, further suggesting a key role for NRF1 in regulation of the SNRPN locus.
Gopalakrishnan and Scarpulla (1995) noted that the electron transport chain and oxidative phosphorylation system rely on the functional interplay of gene products expressed from both nuclear and mitochondrial genomes. Because of the limited coding capacity of the mitochondrial chromosome, nuclear genes must provide most of the respiratory subunits and all of the gene products necessary for mitochondrial DNA transcription and replication. Nuclear respiratory factor-1 (NRF1) is a transcription factor that acts on nuclear genes encoding respiratory subunits and components of the mitochondrial transcription and replication machinery.
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The NRF1 transcription factor binds to 2 palindromic sites within the promoter of the eIF-2-alpha (603907) gene and is essential for eIF-2-alpha transcription. Efiok et al. (1994) cloned human cDNAs encoding NRF1, which they called alpha-Pal.
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... differences in the percentage of alternatively spliced NRF1 pre-mRNA may influence mitochondrial biogenesis under variable physiologic conditions and may play a role in distinct mitochondrial diseases.
Efiok et al. (1994) identified genes containing alpha-Pal-binding sequences and found that these could be classified either as cellular proliferation genes, or as genes regulating the growth-responsive metabolic pathways of energy transduction, translation, and replication. The authors proposed that alpha-Pal [NRF-1] is a transcription factor that links the transcriptional modulation of key metabolic genes to cellular growth and development.
Virbasius and Scarpulla (1994) noted that the nuclear-encoded mitochondrial transcription factor TFAM (600438) contains potential binding sites for NRF1, NRF2 (GABPA; 600609) and SP1 (189906) within the promoter region. With use of binding and electrophoretic mobility shift assays, DNase footprinting, and mutation analysis of recombinant proteins, they demonstrated specific and functional binding of NRF1 and NRF2 to the TFAM promoter region. Methylation of the guanine nucleotides in the tandem GCGC motifs interfered with NRF1 binding. With use of reporter constructs and mutation analysis, they determined that NRF1 has a more robust effect on TFAM promoter activity than NRF2 or SP1. Further, activation by NRF2 or SP1 required the presence of a functional NRF1-binding site.
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Gopalakrishnan and Scarpulla (1995) isolated and characterized the human gene encoding NRF1. The NRF1 gene spans approximately 65 kb and has 11 exons and 10 introns that range in size from 0.8 to 15 kb. The authors noted that these analyses should be useful in evaluating the potential role of NRF1 in mitochondrial diseases resulting from defects in the nuclear control of mitochondrial function.
Impaired oxidative phosphorylation
Muscle biopsies of those with PWS have demonstrated impaired mitochondrial respiratory chain complex I activity (NADH:Q(1) oxidoreductase deficiency, NADH-Coenzyme Q reductase deficiency, mitochondrial NADH dehydrogenase deficiency - OMIM), which presents with hypotonia, weakness, lethargy, dysphagia, failure to thrive, respiratory insufficiency, exercise intolerance, growth and developmental delay, irritability, encephalopathy, encephalomyopathy, strabismus and nystagmus, all of which are present in PWS. However, there has never been any study that has sought to determine if impaired complex I activity is common in PWS and, if so, its cause and what treatments might help ameliorate it.
Muscle biopsies of those with PWS have demonstrated impaired mitochondrial complex IV activity (Cytochrome c oxidase deficiency, COX deficiency - OMIM), which presents with hypotonia, poor suck, lethargy, apathy, failure to thrive, encephalopathy, antenatal and postnatal growth retardation, cognitive impairment, exercise intolerance, and exertional dyspnea, all of which are present in PWS. However, there has never been any study that has sought to determine if impaired complex IV activity is common in PWS and, if so, its cause and what treatments might help ameliorate it.
Pyruvate metabolism
Pyruvate dehydrogenase phosphatase activity (OMIM) presents with neonatal hypotonia, feeding difficulties, and mental and developmental retardation beginning in infancy, all of which are present in PWS. However, there has never been any study that has sought to determine if pyruvate dehydrogenase phosphatase activity is impaired in PWS and, if so, its cause.
Functional energy starvation and elevated ghrelin in PWS
The secretion of ghrelin increases under conditions of negative energy-balance, such as starvation, cachexia, and anorexia nervosa, and elevated ghrelin is found in both starvation and PWS (Hosoda 2006, Milke 2005). However, the possibility that impaired energy substrate utilization leading to a state of functional energy starvation might be a significant causal factor in the elevated ghrelin in PWS does not appear to have been investigated.
Ghrelin and the failure to thrive stage in PWS
In adults, ghrelin is produced by both the stomach and pancreas. However, Hosoda 2006 reports that the amount of ghrelin is very low in fetal stomach and increases in an age-dependent manner. The concentrations of plasma ghrelin also increase postnatally in parallel with the amount of ghrelin produced by the stomach. Hosoda further notes that "[i]nterestingly, the pancreatic ghrelin profile changes dramatically during fetal development; pancreatic ghrelin-expressing cells are numerous from midgestation to the early postnatal period, comprising 10% of all endocrine cells, and decrease in number after birth (50). Ghrelin mRNA expression and ghrelin concentration (mostly des-acyl ghrelin) are markedly elevated in the fetal pancreas, being several times greater than in the fetal stomach." The lack of stomach ghrelin may therefore mean that appetite during the neonatal period and early infancy is primarily reliant on pancreatic ghrelin. However, Stefan 2005 found undetectable levels of insulin and glucagon in neonatal PWS-knockout mice, which suggests there might be a severe impairment in pancreatic exocrine function during the neonatal period and early infancy in PWS. If that is so, it might explain the marked lack of interest in feeding in neonates and young infants with PWS, as they would have little or no stomach or pancreatic ghrelin secretion until ghrelin-producing cells in the stomach begin to develop and the pancreas begins to catch up developmentally, as it apparently does at some point because insulin and glucagon levels do eventually increase.
Growth hormone deficiency in PWS
Functional energy starvation and growth hormone deficiency in PWS
Current medical opinion holds that growth hormone deficiency is very common in PWS because of a central hypothalamic dysfunction. However, growth hormone secretion is also reduced in malnutrition and starvation, so growth hormone deficiency in PWS could also at least in part be due to a state of functional energy starvation due to impaired protein, fat and/or carbohydrate absorption and/or metabolism.
Impaired respiratory function and growth hormone deficiency in PWS
Current medical opinion holds that growth hormone deficiency is very common in PWS because of a central hypothalamic dysfunction. However, impaired respiratory function including hypoventilation and sleep-related breathing disturbances such obstructive sleep apnea are also extremely common in PWS [Camfferman 2006, Priano 2006, Festen 2006, O'Donoghue 2005, Schluter 1997, Arens 1996, Harris 1996, Livingston 1995, Gozal 1994, Clift 1994, Richards 1994, Arens 1994] and it well-established that chronic intermittent hypoxia and sleep fragmentation due to sleep-related breathing disturbances can cause significant abnormalities in the hypothalamus-pituitary-adrenal axis and growth hormone (GH) axis that in turn can result in significantly reduced growth hormone releasing hormone, growth hormone and IGF-1 levels. [Feng 2006, Chiba 1998, Chanoine 1998, Cooper 1995, Grunstein 1989] It is therefore possible that the growth hormone deficiency commonly found in PWS is in some part due to the hypoxia and sleep fragmentation caused by sleep-related breathing disorders also common in PWS, but as far as I can determine, that possibility has not been investigated.
