Thyroid cancer is the most common endocrine malignancy and nonmedullary thyroid carcinoma (NMTC) represents 90% of all cases. NMTC risk in first‐degree relatives of affected cases is elevated ...fivefold to ninefold. Familial NMTC (FNMTC) accounts for about 3–7% of all thyroid tumors and is a more aggressive clinical entity than its sporadic counterparts. Linkage analysis on high‐risk families performed a decade ago mapped several susceptibility loci, but did not lead to the identification of high‐penetrance causal germline mutations. More recently, a genome‐wide association study (GWAS) identified common single nucleotide polymorphisms (SNPs) affecting the risk of sporadic NMTC. We sought to verify if the newly identified genetic risk factors for NMTC are relevant for FNMTC as well. We genotyped 23 SNPs at 11 candidate loci in 672 subjects belonging to 133 pedigrees with at least two NMTC cases. Statistical analysis was performed using family‐based association tests, modified quasi‐likelihood score and logistic‐normal models. SNPs at 9q22.33 near FOXE1 showed convincing evidence of association with NMTC risk in these high‐risk families. The other tested loci resulted negative. These findings confirm the importance of the SNPs identified by recent GWAS on sporadic NMTC on FNMTC as well. However, the proposed FOXE1 causal variants do not show the strongest association signal. Moreover, mutation screening of the FOXE1 coding sequence in the FNMTC cases did not identify rarer causal variants, suggesting that other yet unidentified variants at this locus are involved in FNMTC etiology.
What's new?
Familial thyroid cancer is highly heritable and far more aggressive than the sporadic variety, but so far, no gene has been fingered as the culprit. In this paper, the authors tested several common SNPs that had been linked to sporadic thyroid cancer, and traced the way they travel in families that inherit the disease. One region, near the gene FOXE1, did associate with the disease, but no causal variants have yet been identified.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The English spotting coat color locus in rabbits, also known as Dominant white spotting locus, is determined by an incompletely dominant allele (En). Rabbits homozygous for the recessive wild-type ...allele (en/en) are self-colored, heterozygous En/en rabbits are normally spotted, and homozygous En/En animals are almost completely white. Compared to vital en/en and En/en rabbits, En/En animals are subvital because of a dilated ("mega") cecum and ascending colon. In this study, we investigated the role of the KIT gene as a candidate for the English spotting locus in Checkered Giant rabbits and characterized the abnormalities affecting enteric neurons and c-kit positive interstitial cells of Cajal (ICC) in the megacolon of En/En rabbits. Twenty-one litters were obtained by crossing three Checkered Giant bucks (En/en) with nine Checkered Giant (En/en) and two en/en does, producing a total of 138 F1 and backcrossed rabbits. Resequencing all coding exons and portions of non-coding regions of the KIT gene in 28 rabbits of different breeds identified 98 polymorphisms. A single nucleotide polymorphism genotyped in all F1 families showed complete cosegregation with the English spotting coat color phenotype (θ=0.00 LOD =75.56). KIT gene expression in cecum and colon specimens of En/En (pathological) rabbits was 5-10% of that of en/en (control) rabbits. En/En rabbits showed reduced and altered c-kit immunolabelled ICC compared to en/en controls. Morphometric data on whole mounts of the ascending colon showed a significant decrease of HuC/D (P<0.05) and substance P (P<0.01) immunoreactive neurons in En/En vs. en/en. Electron microscopy analysis showed neuronal and ICC abnormalities in En/En tissues. The En/En rabbit model shows neuro-ICC changes reminiscent of the human non-aganglionic megacolon. This rabbit model may provide a better understanding of the molecular abnormalities underlying conditions associated with non-aganglionic megacolon.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Intellectual disability (ID) and autism spectrum disorders (ASDs) are complex neuropsychiatric conditions, with overlapping clinical boundaries in many patients. We identified a novel intragenic ...deletion of maternal origin in two siblings with mild ID and epilepsy in the CADPS2 gene, encoding for a synaptic protein involved in neurotrophin release and interaction with dopamine receptor type 2 (D2DR). Mutation screening of 223 additional patients (187 with ASD and 36 with ID) identified a missense change of maternal origin disrupting CADPS2/D2DR interaction. CADPS2 allelic expression was tested in blood and different adult human brain regions, revealing that the gene was monoallelically expressed in blood and amygdala, and the expressed allele was the one of maternal origin. Cadps2 gene expression performed in mice at different developmental stages was biallelic in the postnatal and adult stages; however, a monoallelic (maternal) expression was detected in the embryonal stage, suggesting that CADPS2 is subjected to tissue‐ and temporal‐specific regulation in human and mice. We suggest that CADPS2 variants may contribute to ID/ASD development, possibly through a parent‐of‐origin effect.
Synopsis
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
Two rare variants of maternal origin (an intragenic deletion and a missense change) were identified in CADPS2 in a cohort of patients with neurodevelopmental abnormalities; the p. Asp1113Asn variant was shown to disrupt the interaction with dopamine receptor type 2 (D2DR).
Differentially methylated sites were identified in CADPS2 first intron, in blood and amygdala, but they did not show a parent‐of‐origin methylation pattern typical of an imprinted gene.
Tissue‐specific, monoallelic maternal expression of CADPS2 in blood and in the amygdala plays a key role in regulating social interactions and supports the importance of a fine modulation of CADPS2 for human behavior.
CADPS2 variants may contribute to intellectual disability and autism susceptibility, and their role should be interpreted in light of possible parent‐of‐origin effect.
Monoallelic and tissue‐specific expression of novel CADPS2 gene variants was identified in two siblings with borderline cognitive decline and epilepsy, suggesting a role for CADPS2 in intellectual disability and autism spectrum disorders.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Based on a knocked-out mouse model and a few expression studies, TLX3 is regarded as a homeobox gene crucial for the development of the autonomic nervous system. This gene can undergo rearrangements
...or deregulation, giving rise to T-cell acute lymphocytic leukemia. The present report is focused on the identification of
elements and factors playing a role in the TLX3 physiologic expression regulation and therefore likely to be involved in cancer development. In particular, after identifying
the transcription start points, we have made use of in vitro transfection assays to show that the 5′-untranslated region of the gene is necessary for the basal promoter activity in cell
lines from different origin. By site-directed mutagenesis, two tandem CCAAT boxes have been localized as critical elements
of this region. In vivo chromatin immunoprecipitation and electrophoretic mobility shift assays have indicated that nuclear factor Y (NFY) recognizes
these sites in all the analyzed cell lines. The physiologic role of such an interaction has been confirmed by a dominant-negative
version of the NFY transcription factor that has turned out to decrease both in vitro TLX3 promoter activity and endogenous amount of mRNA. Finally, a consistent in vivo TLX3 expression impairment was also achieved after NFY mRNA knockdown. The full characterization of the TLX3 transcription regulation will ultimately provide crucial elements to define the involvement of this gene in T-cell acute
lymphocytic leukemia development. (Mol Cancer Res 2006;4(9):635–43)
TLX2 (also known as HOX11L1, Ncx and Enx) is a transcription factor playing a crucial role in the development of the enteric nervous system, as confirmed by mice models exhibiting intestinal ...hyperganglionosis and pseudo-obstruction. However, congenital defects of TLX2 have been excluded as a major cause of intestinal motility disorders in patients affected with intestinal neuronal dysplasia (IND) or pseudo-obstruction. After demonstrating the direct regulation of TLX2 expression by the homeoprotein PHOX2B, in the present work, we have focused on its paralogue PHOX2A. By co-transfections, electrophoretic mobility shift assays and chromatin immunoprecipitation, we have demonstrated that PHOX2A, like PHOX2B, is involved in the cascade leading to TLX2 transactivation and presumably in the intestinal neuronal differentiation. Based on the hypothesis that missed activation of the TLX2 gene induces the development of enteric nervous system defects, PHOX2A and PHOX2B have been regarded as novel candidate genes involved in IND and pseudo-obstruction and consequently analyzed for mutations in a specific set of 26 patients. We have identified one still unreported PHOX2A variant; however, absence of any functional effect on TLX2 transactivation suggests that regulators or effectors other than the PHOX2 genes must act in the same pathway, likely playing a non redundant and direct role in the pathogenesis of such enteric disorders.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, SIK, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Prucalopride exerts neuroprotection in human enteric neurons Bianco, Francesca; Bonora, Elena; Natarajan, Dipa ...
American journal of physiology. Gastrointestinal and liver physiology/American journal of physiology: Gastrointestinal and liver physiology,
05/2016, Volume:
310, Issue:
10
Journal Article
Peer reviewed
Open access
Serotonin (5-hydroxytryptamine, 5-HT) and its transporters and receptors are involved in a wide array of digestive functions. In particular, 5-HT4 receptors are known to mediate intestinal ...peristalsis and recent data in experimental animals have shown their role in neuronal maintenance and neurogenesis. This study has been designed to test whether prucalopride, a well-known full 5-HT4 agonist, exerts protective effects on neurons, including enteric neurons, exposed to oxidative stress challenge. Sulforhodamine B assay was used to determine the survival of SH-SY5Y cells, human enteric neurospheres, and ex vivo submucosal neurons following H2O2 exposure in the presence or absence of prucalopride (1 nM). Specificity of 5-HT4-mediated neuroprotection was established by experiments performed in the presence of GR113808, a 5-HT4 antagonist. Prucalopride exhibited a significant neuroprotective effect. SH-SY5Y cells pretreated with prucalopride were protected from the injury elicited by H2O2 as shown by increased survival (73.5 ± 0.1% of neuronal survival vs. 33.3 ± 0.1%, respectively; P < 0.0001) and a significant reduction of proapoptotic caspase-3 and caspase-9 activation in all neurons tested. The protective effect of prucalopride was reversed by the specific 5-HT4 antagonist GR113808. Prucalopride promotes a significant neuroprotection against oxidative-mediated proapoptotic mechanisms. Our data pave the way for novel therapeutic implications of full 5-HT4 agonists in gut dysmotility characterized by neuronal degeneration, which go beyond the well-known enterokinetic effect.
Context: RET is a tyrosine kinase transmembrane receptor expressed in two main alternative isoforms: RET9 and RET51. RET transduces a positive signal leading to survival, differentiation, or ...migration in the presence of its ligand glial cell line-derived neurotrophic factor, whereas in its absence a proapoptotic fragment that initiates a negative signaling for apoptosis is generated. The signal transduction mechanisms leading to apoptosis are still unclear.
Objective: To shed light on the mechanisms of RET-induced apoptosis, we searched for novel interactors of RET51.
Design: The “split ubiquitin yeast two-hybrid system” was used with RET51 as bait against a human brain expression library.
Results: We identified aryl hydrocarbon receptor-interacting protein (AIP), a cochaperone recently found mutated in pituitary adenoma patients, as a novel interactor of RET. We showed that RET interacts specifically with AIP both in mammalian cell lines and in vivo in the pituitary gland, regardless of the presence of pituitary adenoma-specific mutations. AIP and RET genes were sequenced in 28 pituitary adenoma, but no relevant mutations were found. In addition, we identified the proapoptotic domain of RET as responsible for the interaction with AIP. Finally, we demonstrated that the AIP-RET interaction does not require RET kinase activity or kinase-dependent signal transduction and that it prevents the formation of the AIP-survivin complex.
Conclusions: The identification of the AIP-RET complex represents a starting point to study key cellular processes involved in RET-induced apoptosis.
The identification of the aryl hydrocarbon receptor interacting protein-RET complex represents a starting point to study key cellular processes involved in RET induced apoptosis.
Fatness in pigs is a complex trait for which a large number of genes are expected to be involved. Genetics of human obesity could take advantages from genetic information coming from the pig and vice ...versa. To these aims, a comprehensive candidate gene approach could be helpful. We catalogued all genes affecting fatness on both species, and identified in silico and by resequencing porcine SNPs on a large number of candidate genes. In addition, we applied a selective genotyping approach to identify markers associated with fat deposition in pigs. This approach was tested genotyping the IGF2 intron3-g.3072G>A mutation and novel markers in the PCSK1 and TBC1D1 genes. Polymorphisms in these genes resulted associated with back fat thickness in Italian Large White pigs.
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