Copy number variation and Huntington’s disease

Tese de doutoramento, Ciências Biomédicas (Neurociências), Universidade de Lisboa, Faculdade de Medicina, 2014Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by the expansion of an unstable triplet repeat within the huntingtin gene. The length of this repeat is inversely correlated with the age of onset (AO) of the disease, which ranges from 1 to 80 years of age. The length of this repeat explains 50-70% of the variance of AO with the remaining variation attributable to environmental and other genetic factors. Copy number variation (CNV) is a structural variation of the human genome wherein a genomic sequence is duplicated or deleted compared to a reference genome. As CNVs have the potential to affect gene expression either directly by dosage effects or indirectly by affecting gene product interactions and pleiotropic effects, they are found to be associated with phenotypic variance, disease susceptibility and Mendelian disorders. The aim of the study was to investigate CNVs as candidate genetic modifiers of the AO in HD. Specifically we investigated CNV of the human β-defensin region (including DEFB4) and CNV involving SLC2A3, with potential impacts, respectively, in the neuroinflammatory response and in neuronal glucose uptake. CNVs were analysed within a large HD sample cohort (provided by EHDN) using the paralogue ratio test (PRT) to test their potential impact on a variance of the AO in HD. In 490 HD individuals analysed the frequency distribution of β-defensin copy number was shown to be equivalent to the general European population. Furthermore, no significant association was shown between β-defensin CNV and a variance of the AO in HD. 987 HD patients were genotyped for SLC2A3 CNV and a modest but significant association with a variance of AO in HD was found (p value = 0.028). Individuals with three copies showed a delay in the AO of up to nearly 6 years compared to individuals with one or two copies. In order to test if SLC2A3 CNV affects gene expression 15 cell lines from patients with different SLC2A3 copy number were immunoblotted for GLUT3 (encoded by SLC2A3) and it was found that the protein level was significantly correlated with the genomic copy number (p value = 0.020). Therefore, we concluded that SLC2A3 CNV is a genetic modifier of the AO in HD, associated to a variance of the disease onset and affecting the gene expression. To investigate the functional basis of this effect, we analysed lines showing over- or under-expression of the functional homolog of SLC2A3 (Glut1) in a Drosophila model of HD. After analysing several disease-relevant metrics, including neurodegeneration of the photoreceptors, eclosion rate and longevity, we found that gain and loss of Glut1 expression can delay and worsen, respectively, neurodegeneration in HD flies. In conclusion, β-defensin genomic copy number is not associated with modulation of HD AO. On the other hand, SLC2A3 CNV is a genetic modifier of the AO in HD, and likely has functional consequences, based on our findings in patient cells and in a Drosophila HD model

A polymorphic variant of the insulin-like growth factor 1 (IGF-1) receptor correlates with male longevity in the Italian population: a genetic study and evaluation of circulating IGF-1 from the "Treviso Longeva (TRELONG)" study

<p>Abstract</p> <p>Background</p> <p>An attenuation of the insulin-like growth factor 1 (IGF-1) signaling has been associated with elongation of the lifespan in simple metazoan organisms and in rodents. In humans, IGF-1 level has an age-related modulation with a lower concentration in the elderly, depending on hormonal and genetic factors affecting the IGF-1 receptor gene (<it>IGF-1R</it>).</p> <p>Methods</p> <p>In an elderly population from North-eastern Italy (<it>n </it>= 668 subjects, age range 70–106 years) we investigated the <it>IGF-1R </it>polymorphism G3174A (<it>rs2229765</it>) and the plasma concentration of free IGF-1. Frequency distributions were compared using χ²-test "Goodness of Fit" test, and means were compared by one-way analysis of variance (ANOVA); multiple regression analysis was performed using JMP7 for SAS software (SAS Institute, USA). The limit of significance for genetic and biochemical comparison was set at α = 0.05.</p> <p>Results</p> <p>Males showed an age-related increase in the A-allele of <it>rs2229765 </it>and a change in the plasma level of IGF-1, which dropped significantly after 85 years of age (85+ group). In the male 85+ group, A/A homozygous subjects had the lowest plasma IGF-1 level. We found no clear correlation between <it>rs2229765 </it>genotype and IGF-1 in the females.</p> <p>Conclusion</p> <p>These findings confirm the importance of the <it>rs2229765 </it>minor allele as a genetic predisposing factor for longevity in Italy where a sex-specific pattern for IGF-1 attenuation with ageing was found.</p

β-defensin genomic copy number does not influence the age of onset in Huntington’s disease

Background: Huntington’s disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammation is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2) – encoded by DEFB4 – is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD. Objective: In this study we tested the hypothesis that copy number variation (CNV) of the β-defensin region, including DEFB4, modifies the AO in HD. Methods and results: We genotyped β-defensin CNV in 490 HD individuals using the paralogue ratio test and found no association between β-defensin CNV and onset of HD. Conclusions: We conclude that it is unlikely that DEFB4 plays a role in HD pathogenesis

β-Defensin genomic copy number does not influence the age of onset in Huntington's Disease

BACKGROUND: Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammations is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2)- encoded by DEFB4- is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD. OBJECTIVE: In this study we tested the hypothesis that copy number variation (CNV) of the β-defensin region, including DEFB4, modifies the AO in HD. METHODS AND RESULTS: We genotyped β-defensin CNV in 490 HD individuals using the paralogue ratio test and found no association between β-defensin CNV and onset of HD. CONCLUSIONS: We conclude that it is unlikely that DEFB4 plays a role in HD pathogenesis

Copy-number variation of the neuronal glucose transporter gene SLC2A3 and age of onset in Huntington&apos;s disease

Huntington&apos;s disease (HD) is a devastating neurodegenerative disorder which is inherited in an autosomal dominant manner. HD is caused by a trinucleotide CAG repeat expansion that encodes a polyglutamine stretch in the huntingtin (HTT) protein. Mutant HTT expression leads to a myriad of cellular dysfunctions culminating in neuronal loss and consequent motor, cognitive and psychiatric disturbances in HD patients. The length of the CAG repeat is inversely correlated with age of onset (AO) in HD patients, while environmental and genetic factors can further modulate this parameter. Here, we explored whether the recently described copy-number variation (CNV) of the gene SLC2A3-which encodes the neuronal glucose transporter GLUT3-could modulate AO in HD. Strikingly, we found that increased dosage of SLC2A3 delayed AO in an HD cohort of 987 individuals, and that this correlated with increased levels of GLUT3 in HD patient cells. To our knowledge this is the first time that CNV of a candidate gene has been found to modulate HD pathogenesis. Furthermore, we found that increasing dosage of Glut1-the Drosophila melanogaster homologue of this glucose transporter-ameliorated HD-relevant phenotypes in fruit flies, including neurodegeneration and life expectancy. As alterations in glucose metabolism have been implicated in HD pathogenesis, this study may have important therapeutic relevance for HD

β-Defensin Genomic Copy Number Does Not Influence the Age of Onset in Huntington's Disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder caused by the abnormal expansion of a CAG triplet repeat tract in the huntingtin gene. While the length of this CAG expansion is the major determinant of the age of onset (AO), other genetic factors have also been shown to play a modulatory role. Recent evidence suggests that neuroinflammation is a pivotal factor in the pathogenesis of HD, and that targeting this process may have important therapeutic ramifications. The human β-defensin 2 (hBD2) - encoded by DEFB4 - is an antimicrobial peptide that exhibits inducible expression in astrocytes during inflammation and is an important regulator of innate and adaptive immune response. Therefore, DEFB4 may contribute to the neuroinflammatory processes observed in HD

Phase i trial of oral mTOR inhibitor everolimus in combination with trastuzumab and vinorelbine in pre-treated patients with HER2-overexpressing metastatic breast cancer

To determine the feasible dose and schedule for everolimus, an oral mTOR inhibitor, combined with vinorelbine and trastuzumab for patients with HER2-overexpressing metastatic breast cancer pretreated with trastuzumab. In this phase Ib multicenter, Bayesian dose-escalation study, 50 patients received everolimus 5 mg/day, 20 mg/week, or 30 mg/week plus vinorelbine (25 mg/m 2 on day 1 and 8 every 3 weeks) and trastuzumab (2 mg/kg weekly). Endpoints included end-of-cycle-1 dose-limiting toxicity (DLT) rate (primary endpoint), safety, relative dose intensity, overall response rate (ORR), and pharmacokinetics. Grade 3/4 neutropenia was the most common end-of-cycle-1 DLT and occurred in 10 of 30 and 4 of 14 patients in the 5 mg/day and 30 mg/week cohorts, respectively. Other end-of-cycle-1 DLTs included single cases of febrile neutropenia, grade 3 stomatitis with concomitant fatigue, grade 2 stomatitis, grade 3 anorexia, and grade 2 acneiform dermatitis, all in the 5-mg/day cohort. Based on the recorded DLTs and global safety, everolimus 5 mg/day and 30 mg/week were chosen as the optimal dose levels for the daily and weekly arms. Forty-seven patients were evaluable for efficacy. ORR was 19.1%, with a disease control rate of 83.0% and median progression-free survival of 30.7 weeks. No drug interaction was observed between everolimus and vinorelbine. Everolimus combined with weekly vinorelbine and trastuzumab generally was well tolerated and had encouraging antitumor activity in heavily pretreated patients with HER2-overexpressing metastatic breast cancer that progressed on trastuzumab (NCT00426530). © 2010 Springer Science+Business Media, LLC.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic

International audienceAbstract The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic. Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases

Consensus statement of the Italian society of pediatric allergy and immunology for the pragmatic management of children and adolescents with allergic or immunological diseases during the COVID-19 pandemic

The COVID-19 pandemic has surprised the entire population. The world has had to face an unprecedented pandemic. Only, Spanish flu had similar disastrous consequences. As a result, drastic measures (lockdown) have been adopted worldwide. Healthcare service has been overwhelmed by the extraordinary influx of patients, often requiring high intensity of care. Mortality has been associated with severe comorbidities, including chronic diseases. Patients with frailty were, therefore, the victim of the SARS-COV-2 infection. Allergy and asthma are the most prevalent chronic disorders in children and adolescents, so they need careful attention and, if necessary, an adaptation of their regular treatment plans. Fortunately, at present, young people are less suffering from COVID-19, both as incidence and severity. However, any age, including infancy, could be affected by the pandemic.Based on this background, the Italian Society of Pediatric Allergy and Immunology has felt it necessary to provide a Consensus Statement. This expert panel consensus document offers a rationale to help guide decision-making in the management of children and adolescents with allergic or immunologic diseases