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Overview of the snoRNA expression region on chromosome 15. RNase protection analysis of 10 μg frontal cortex RNA from PWS patients and control patients.
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Prader-Willi syndrome (PWS) is caused by the loss of RNA expression from an imprinted region on chromosome 15 that includes SNRPN, SNORD115, and SNORD116. Currently, there are no mouse models that faithfully reflect the human phenotype and investigations rely on human post-mortem material. During molecular characterization of tissue deposited in a...
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... To test whether SNORD115 is also expressed in pituitary, we first used RT-PCR and detected SNORD115 in both the anterior and posterior pituitary as well as in the pituitary stalk (Fig. 2C). To test SNORD115 expression with a different method that will not detect possible DNA contaminants, we used RNase protection analysis and human samples, employing a probe against human SNORD115 [14,15]. We used frontal cortex from PWS subjects and human controls for comparison. ...
... Prader-Willi syndrome (PWS) is probably the best understood example of a disease involving snoRNA mutation. PWS is the result of the complete loss of the paternally inherited region 15q11-q13 of chromosome 15 [34]. This region contains 47 and 28 tandem repeats of the box C/D snoRNAs called SNORD115 and SNORD116 respectively [35]. ...
Many human diseases have been attributed to mutation in the protein coding regions of the human genome. The protein coding portion of the human genome, however, is very small compared with the non-coding portion of the genome. As such, there are a disproportionate number of diseases attributed to the coding compared with the non-coding portion of the genome. It is now clear that the non-coding portion of the genome produces many functional non-coding RNAs and these RNAs are slowly being linked to human diseases. Here we discuss examples where mutation in classical non-coding RNAs have been attributed to human disease and identify the future potential for the non-coding portion of the genome in disease biology.
* CHH, : cartilage-hair hypoplasia; DC, : dyskeratosis congenital; MELAS, : mitochondrial myopathy, encephalopathy, lactic acidosis and stroke-like episodes; MERRF, : myoclonic epilepsy with ragged red fibres; MOPD1, : microcephalic osteodysplastic primordial dwarfism type 1; MRP, : mitochondrial RNA processing; mt-tRNA, : mitochondrial tRNA; pre-mRNA, : pre-messenger RNA; PWS, : Prader–Willi syndrome; snoRNA, : small nucleolar RNA; SNP, : single nucleotide polymorphism; snRNA, : small nuclear RNA; snRNP, : small nuclear ribonucleoprotein particle; TERC, : telomerase RNA component; TERT, : telomerase reverse transcriptase
... Were performed as previously described [47,48] using a probe against pri-miR-194 (hg19: chr11:64,658,827-64,658,911) and 40 µg of HEK293 total RNA and 80,000 cpm of 32 P-labeled probe, generated with alpha UTP (800 Ci/mmol) as the only source of UTP. ...
Valproic acid (VPA) is a commonly used drug to treat epilepsy and bipolar disorders. Known properties of VPA are inhibitions of histone deacetylases and activation of extracellular signal regulated kinases (ERK), which cannot fully explain VPA's clinical features. We found that VPA induces the proteasomal degradation of DICER, a key protein in the generation of micro RNAs. Unexpectedly, the concentration of several micro RNAs increases after VPA treatment, which is caused by the upregulation of their hosting genes prior to DICER degradation. The data suggest that a loss of DICER protein and changes in micro RNA concentration contributes to the clinical properties of VPA. VPA can be used experimentally to down regulate DICER protein levels, which likely reflects a natural regulation of DICER.
Prader–Willi syndrome (PWS) is a complex neurodevelopmental disorder, arising from a loss of paternity expressed genetic material on the imprinted chromosome locus 15q11-q13. Despite increasing clarity on the underlying genetic defects, the molecular basis of the condition remains poorly understood.
Hypothalamic dysfunction is widely recognized as the basis of the core symptoms of PWS, which include a deficiency in growth hormone and reproductive hormones, circadian rhythm abnormalities, and a lack of satiety, leading to an extreme obesity, among others.
Genome-wide gene expression analysis (transcriptomics) offers an unbiased interrogation of complex disease pathogenesis and a potential window into the dysregulated pathways involved in disease. In this chapter, we review the findings from recent work investigating the PWS hypothalamic transcriptome, discuss the significance of the findings in relation to the clinical presentation and molecular underpinnings of PWS, and highlight future research directions.
Introduction: Prader-Willi syndrome is a genetic disorder caused by deleted or unexpressed genes contained in 15q11-q13 region of paternal chromosome. Objective: to describe clinical and genetic characteristics of patients with Prader-Willi syndrome. Material and method: a descriptive, cross-sectional study was conducted in 15 patients with Prader-Willi suspect, who were referred to the provincial office of Clinical Genetics during 2013. As clinical variables the diagnostic criteria of Holms were considered and as genetic variables, the results of chromosomal and molecular studies. Results: female sex prevailed in 66.7%. Ages were between 3 and 41. Most frequent major criteria were troncular obesity and neurodevelopment retardation in 100% of the patients. The minor criteria more identified were: sleep disturbances and speech difficulties (66.7% each one). None of the cases presented chromosomal anomalies because of karyotype classification. Three patients (60%) presented deletion at 15q11-q13 region level, which was identified by hybridization in situ with fluorescence. Conclusions: in the province a definitive diagnosis was delayed. A reassessment is required according to the clinical criteria during the different stages of life in order to achieve a definitive diagnosis. The presence of neonatal hypotonia and difficulties in feeding are associated elements to the diagnosis of 15q11-q13 deletion.
In many inherited genetic diseases short stature very frequently represents a serious psycho-logical problem and the cause of social adaptation failure or dysadaptation. Small stature is the most common feature of Shereshevsky-Turner syndrome. The occurrence rate of this syndrome is 1 case per 2,000-2,500 of live-born girls. The disease is of sporadic character. The triad of signs is typical of the mentioned pathology: short height, gonad dysgenesia and various organ con-genital anomalies. The cases of stunting are Prader-Willi syndrome, Noonan syndrome, Silver-Russell syndrome, Cornelia de Lange syndrome. Development of genetically engineered method for obtaining recombinant growth hormone has triggered a real revolution in treatment of chil-dren with various forms of stunting. Particularly, an opportunity to increase growth rate in chil-dren has appeared, thereby improving growth prognosis. The patients with genetically deter-mined stunting have a high incidence of congenital malformations and presence of various co-morbidities, which require life-long monitoring by various health professionals. Observation of patients with the above syndromes must be comprehensive and should take into account different age-related needs. Timely medical intervention in the precise group of patients significantly re-duces the risk of early morbidity and mortality and improves the quality of life. The challenges of early diagnosis with the use of modern methods of investigation remain unresolved and deter-mine the relevance of the problem.
The loss of two gene clusters encoding small nucleolar RNAs, SNORD115 and SNORD116 contributes to Prader-Willi syndrome (PWS), the most common syndromic form of obesity in humans. SNORD115 and SNORD116 are considered to be orphan C/D box snoRNAs (SNORDs) as they do not target rRNAs or snRNAs. SNORD115 exhibits sequence complementarity towards the serotonin receptor 2C, but SNORD116 shows no extended complementarities to known RNAs. To identify molecular targets, we performed genome-wide array analysis after overexpressing SNORD115 and SNORD116 in HEK 293T cells, either alone or together. We found that SNORD116 changes the expression of over 200 genes. SNORD116 mainly changed mRNA expression levels. Surprisingly, we found that SNORD115 changes SNORD116's influence on gene expression. In similar experiments, we compared gene expression in post-mortem hypothalamus between individuals with PWS and aged-matched controls. The synopsis of these experiments resulted in 23 genes whose expression levels were influenced by SNORD116. Together our results indicate that SNORD115 and SNORD116 influence expression levels of multiple genes and modify each other activity.
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Previous studies have identified an area in the left lateral fusiform cortex that is highly responsive to written words and has been named the visual word form area (VWFA). However, there is disagreement on the specific functional role of this area in word recognition. Chinese characters, which are dramatically different from Roman alphabets in the visual form and in the form to phonological mapping, provide a unique opportunity to investigate the properties of the VWFA. Specifically, to clarify the orthographic sensitivity in the mid-fusiform cortex, we compared fMRI response amplitudes (Exp. 1) as well as the spatial patterns of response across multiple voxels (Exp. 2) between Chinese characters and stimuli derived from Chinese characters with different orthographic properties. The fMRI response amplitude results suggest the existence of orthographic sensitivity in the VWFA. The results from multi-voxel pattern analysis indicate that spatial distribution of the responses across voxels in the occipitotemporal cortex contained discriminative information between the different types of character-related stimuli. These results together suggest that the orthographic rules are likely represented in a distributed neural network with the VWFA containing the most specific information regarding a stimulus' orthographic regularity.
The serotonin receptor 2C (HTR2C) gene encodes a G protein-coupled receptor that is exclusively expressed in neurons. Here, we report that the 5′ untranslated region of the receptor pre-mRNA as well as its hosted miRNAs is widely expressed in non-neuronal cell lines. Alternative splicing of HTR2C is regulated by MBII-52. MBII-52 and the neighboring MBII-85 cluster are absent in people with Prader–Willi syndrome, which likely causes the disease. We show that MBII-52 and MBII-85 increase expression of the HTR2C 5′ UTR and influence expression of the hosted miRNAs. The data indicate that the transcriptional unit expressing HTR2C is more complex than previously recognized and likely deregulated in Prader–Willi syndrome.
Electronic supplementary material
The online version of this article (doi:10.1007/s00221-013-3458-8) contains supplementary material, which is available to authorized users.
