Color vision defects (CVDs) are conditions characterized by the alteration of normal trichromatic vision. CVDs can arise as the result of alterations in three genes (
,
,
) or as a combination of ...genetic predisposition and environmental factors. To date, apart from Mendelian CVDs forms, nothing is known about multifactorial CVDs forms.
Five hundred and twenty individuals from Silk Road isolated communities were genotyped and phenotypically characterized for CVDs using the Farnsworth D-15 color test. The CVDs traits Deutan-Protan (DP) and Tritan (TR) were analysed. Genome Wide Association Study for both traits was performed, and results were corrected with a False Discovery Rate linkage-based approach (FDR-p). Gene expression of final candidates was investigated using a published human eye dataset, and pathway analysis was performed.
Concerning DP, three genes:
(FDR-p: 9.01*10
),
(FDR-p: 4.97*10
) and
(FDR-p: 4.98*10
), stood out as promising candidates.
is involved in the preservation of Retinal Pigmented Epithelium (RPE) homeostasis while
and
are both involved in visual signal transmission. With regards to TR, four genes:
(FDR-p: 4.09*10
),
(FDR-p: 6,52*10
),
(FDR-p: 8.34*10
), and
(FDR-p: 2.10*10
), were considered promising candidates.
is reported to be associated with Retinitis pigmentosa;
is reported to regulate choroidal vascularization in Age-Related Macular Degeneration;
is involved in RPE homeostasis regulation;
is reported to regulate lacrimal gland function.
Overall, these results provide novel insights regarding a complex phenotype (i.e., CVDs) in an underrepresented population such as Silk Road isolated communities.
Endometriosis (EM) is defined as the engraftment and proliferation of functional endometrial-like tissue outside the uterine cavity, leading to a chronic inflammatory condition. While the precise ...etiology of EM remains elusive, recent studies have highlighted the crucial involvement of a dysregulated immune system. The complement system is one of the predominantly altered immune pathways in EM. Owing to its involvement in the process of angiogenesis, here, we have examined the possible role of the first recognition molecule of the complement classical pathway, C1q. C1q plays seminal roles in several physiological and pathological processes independent of complement activation, including tumor growth, placentation, wound healing, and angiogenesis. Gene expression analysis using the publicly available data revealed that C1q is expressed at higher levels in EM lesions compared to their healthy counterparts. Immunohistochemical analysis confirmed the presence of C1q protein, being localized around the blood vessels in the EM lesions. CD68 + macrophages are the likely producer of C1q in the EM lesions since cultured EM cells did not produce C1q in vitro . To explore the underlying reasons for increased C1q expression in EM, we focused on its established pro-angiogenic role. Employing various angiogenesis assays on primary endothelial endometriotic cells, such as migration, proliferation, and tube formation assays, we observed a robust proangiogenic effect induced by C1q on endothelial cells in the context of EM. C1q promoted angiogenesis in endothelial cells isolated from EM lesions (as well as healthy ovary that is also rich in C1q). Interestingly, endothelial cells from EM lesions seem to overexpress the receptor for the globular heads of C1q (gC1qR), a putative C1q receptor. Experiments with siRNA to silence gC1qR resulted in diminished capacity of C1q to perform its angiogenic functions, suggesting that C1q is likely to engage gC1qR in the pathophysiology of EM. gC1qR can be a potential therapeutic target in EM patients that will disrupt C1q-mediated proangiogenic activities in EM.
Usher syndrome (USH) is an autosomal recessive disorder characterized by sensorineural hearing loss (HL), retinopathy, and vestibular areflexia, with variable severity. Although a high prevalence of ...behavioural and mental disorders in USH patients has been reported, few studies on these psychiatric and psychological issues have been conducted. This work describes the case of a 16-year-old boy affected by congenital bilateral sensorineural HL, presenting a suddenly altered behaviour concomitant with a decrease in visual acuity. To establish a molecular diagnosis, Whole-Exome Sequencing analysis was performed, detecting a pathogenetic homozygous variant (c. 5985C>A, p.(Tyr1995*)) within the CDH23 gene. CDH23 is a known USH type 1 causative gene, recently associated with schizophrenia-like symptoms and bipolar disorders. To date, no studies have provided evidence of a direct genotype–phenotype correlation between USH patients carrying CDH23 variants and mental/behavioural issues; however, considering the multiple biological functions of CDH23, it can be hypothesised that it could have a pleiotropic effect. Overall, this study highlights the relevance of a continuous clinical evaluation of USH patients, to monitor not only the disease progression, but to early detect any psychological or behavioural alterations, thus allowing a rapid implementation of therapeutic strategies aimed at improving their quality of life and well-being.
Chromatin organization plays a crucial role in tissue homeostasis. Heterochromatin relaxation and consequent unscheduled mobilization of transposable elements (TEs) are emerging as key contributors ...of aging and aging-related pathologies, including Alzheimer’s disease (AD) and cancer. However, the mechanisms governing heterochromatin maintenance or its relaxation in pathological conditions remain poorly understood. Here we show that PIN1, the only phosphorylation-specific cis/trans prolyl isomerase, whose loss is associated with premature aging and AD, is essential to preserve heterochromatin. We demonstrate that this PIN1 function is conserved from Drosophila to humans and prevents TE mobilization-dependent neurodegeneration and cognitive defects. Mechanistically, PIN1 maintains nuclear type-B Lamin structure and anchoring function for heterochromatin protein 1α (HP1α). This mechanism prevents nuclear envelope alterations and heterochromatin relaxation under mechanical stress, which is a key contributor to aging-related pathologies.
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•PIN1 stabilizes HP1α in complex with LaminB in a phosphorylation-dependent manner•PIN1 function maintains nuclear envelope structure under mechanical stress•PIN1 loss causes HP1α degradation, heterochromatin relaxation, transposon derepression•Loss of PIN1 nucleo-protective function contributes to Alzheimer’s disease
In aging-related diseases, heterochromatin becomes relaxed through poorly understood mechanisms, which makes cells prone to genome damage and death. Napoletano et al. find a mechanism of signal transduction through the nuclear envelope that maintains nuclear architecture and safeguards heterochromatin under mechanical stress and is impaired in neurodegenerative diseases.
Dual molecular diagnoses are defined as the presence of pathogenic variants at two distinct and independently segregating loci that cause two different Mendelian conditions. In this study, we report ...the identification of double genetic disorders in a series of patients with complex clinical features. In the last 24 months, 342 syndromic patients have been recruited and clinically characterised. Whole Exome Sequencing analysis has been performed on the proband and on both parents and identified seven patients affected by a dual molecular diagnosis. Upon a detailed evaluation of both their clinical and molecular features, subjects are able to be divided into two groups: (A) five patients who present distinct phenotypes, due to each of the two different underlying genetic diseases; (B) two patients with overlapping clinical features that may be underpinned by both the identified genetic variations. Notably, only in one case a multilocus genomic variation was already suspected during the clinical evaluation. Overall, our findings highlight how dual molecular diagnoses represent a challenging model of complex inheritance that should always be considered whenever a patient shows atypical clinical features. Indeed, an accurate genetic characterisation is of the utmost importance to provide patients with a personalised and safe clinical management.
Bruxism is a worldwide oral health problem. Although there is a consensus about its multifactorial nature, its precise etiopathogenetic mechanisms are unclear. This study, taking advantage of a ...deeply characterized cohort of 769 individuals (aged 6-89 years) coming from Northern Italy's genetically isolated populations, aims to epidemiologically describe environmental risk factors for bruxism development and identify genes potentially involved through a Genome-Wide Association Study (GWAS) approach. Logistic mixed models adjusted for age and sex were performed to evaluate associations between bruxism and possible risk factors, e.g., anxiety, smoking, and alcohol and caffeine intake. A case-control GWAS (135 cases, 523 controls), adjusted for age, sex, and anxiety, was conducted to identify new candidate genes. The GTEx data analysis was performed to evaluate the identified gene expression in human body tissues. Statistical analyses determined anxiety as a bruxism risk factor (OR = 2.54; 95% CI: 1.20-5.38;
-value = 0.015), and GWAS highlighted three novel genes potentially associated with bruxism:
(topSNP = rs2046718;
-value = 2.63 × 10
),
(topSNP = rs571497947;
-value = 4.68 × 10
), and
(topSNP = rs2324342;
-value = 7.47 × 10
). The GTEx data analysis showed their expression in brain tissues. Overall, this work provided a deeper understanding of bruxism etiopathogenesis with the long-term perspective of developing personalized therapeutic approaches for improving affected individuals' quality of life.
The innate immune system is crucial in fighting SARS-CoV-2 infection, which is responsible for coronavirus disease 2019 (COVID-19). Therefore, deepening our understanding of the underlying immune ...response mechanisms is fundamental for the development of novel therapeutic strategies. The role of extra-oral bitter (TAS2Rs) and sweet (TAS1Rs) taste receptors in immune response regulation has yet to be fully understood. However, a few studies have investigated the association between taste receptor genes and COVID-19 symptom severity, with controversial results. Therefore, this study aims to deepen the relationship between COVID-19 symptom presence/severity and
and
(
member) genetic variations in a cohort of 196 COVID-19 patients. Statistical analyses detected significant associations between rs307355 of the
gene and the following COVID-19-related symptoms: chest pain and shortness of breath. Specifically, homozygous C/C patients are exposed to an increased risk of manifesting severe forms of chest pain (OR 8.11, 95% CI 2.26-51.99) and shortness of breath (OR 4.83, 95% CI 1.71-17.32) in comparison with T/C carriers. Finally, no significant associations between the
haplotype and the presence/severity of COVID-19 symptoms were detected. This study, taking advantage of a clinically and genetically characterised cohort of COVID-19 patients, revealed
gene involvement in determining COVID-19 symptom severity independently of
activity, thus providing novel insights into the role of TAS1Rs in regulating the immune response to viral infections.
Malocclusions and temporomandibular disorders (TMDs) are oral health problems that are spread worldwide. To date, few studies focused on their prevalence and associated risk factors are available. ...This study aims to define the prevalence and distribution of odontostomatological traits and evaluate specific risk factors in isolated villages in north-eastern Italy, taking advantage of their environmental homogeneity. Nine hundred and forty-four participants aged six to eighty-nine years were enrolled. Thirty-one odontostomatological phenotypes, classified into five domains (airways, bad habits, extraoral and intraoral parameters, TMDs, and teeth), were evaluated. A descriptive statistical analysis was performed; mixed logistic models were used to test the relationships among the traits. According to the study's findings, Angle's class I was prevalent (65.3%) followed by class II malocclusion (24.3%); class III and reversed overjet were the least frequent malocclusions (10.4% and 1.8%, respectively). Temporomandibular joint (TMJ) click/noise was prevalent among TMDs (34.7%). The statistically significant (
-value < 0.05) risk factors were ankyloglossia for phonetic issues (OR 1.90) and bruxism for TMJ click/noise (OR 1.70) and pain (OR 2.20). Overall, this work provides a picture of the prevalence of malocclusions and TMDs in a large Italian sample and reveals risk factors to take into account in the development of preventive strategies and treatments.
Eating behavior (EB) is a complex system influenced by many factors, but an undisputed role is played by the senses. In this work, we examined the effect of the sensory capacities on EB in 1152 ...Italian adult individuals. After administering a questionnaire on EB and assessing sensory performance through standard audiometric, olfactory, and taste tests, the prevalence of reduced sensory capacities (RSCs) and the correlation with selected risk factors were calculated. Regression models, structural equation modelling, and conditional recursive partitioning were used to investigate the relationship between variables. Around 70% of the subjects show reduced capacities in at least one sense, with taste being the most prevalent (55.21%). Male sex, aging, and low educational level are risk factors for RSCs. The increased number of senses with reduced capacities is a predictor of diminished food adventurousness and lower liking for vegetables, fish, and alcoholic beverages, while reduced capacities (RCs) in taste is a predictor of lower liking for alcoholic beverages and sweets. Overall, in addition to providing an overall picture of RSCs in Italian samples, our study reveals the association of RSCs with EB variables. This finding could have a relevant role in influencing individuals' dietary habits and, therefore, health status.
Hearing loss is the most frequent sensorineural disorder, affecting approximately 1:1000 newborns. Hereditary forms (HHL) represent 50-60% of cases, highlighting the relevance of genetic testing in ...deaf patients. HHL is classified as non-syndromic (NSHL-70% of cases) or syndromic (SHL-30% of cases). In this study, a multistep and integrative approach aimed at identifying the molecular cause of HHL in 102 patients, whose
analysis already showed a negative result, is described. In NSHL patients, multiplex ligation probe amplification and long-range PCR analyses of the
gene solved 13 cases, while whole exome sequencing (WES) identified the genetic diagnosis in 26 additional ones, with a total detection rate of 47.6%. Concerning SHL, WES detected the molecular cause in 55% of cases. Peculiar findings are represented by the identification of four subjects displaying a dual molecular diagnosis and eight affected by non-syndromic mimics, five of them presenting Usher syndrome type 2. Overall, this study provides a detailed characterisation of the genetic causes of HHL in the Italian population. Furthermore, we highlighted the frequency of Usher syndrome type 2 carriers in the Italian population to pave the way for a more effective implementation of diagnostic and follow-up strategies for this disease.
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