1,721,242 research outputs found
Genetics of hearing loss (from congenital forms to presbycusis)
No full textSince the identification of the first deafness gene in the '90s, a relevant number of genes have been identified. This finding led to a significant increase on the molecular knowledge of the processes responsible for hearing and balance and of the corresponding pathological mechanisms. But there is still a long way to go and many genes remain to be identified. The elucidation of the exact function of genes for which only a putative function has been hypothesized and of genes with an unknown function, remains a great challenge. In this chapter an up-to-day overview on the genetics of hearing loss is provided to the reader
A novel P2RX2 mutation in an Italian family affected by autosomal dominant nonsyndromic hearing loss
No full textHereditary hearing loss (HHL) is a common disorder accounting for at least 60% of prelingual deafness. It is characterized by a large genetic heterogeneity, and despite the presence of a major gene, still there is a need to search for new causative mutations/genes. Very recently, a mutation within ATP-gated P2X(2) receptor (ligand-gated ion channel, purinergic receptor 2) gene (P2RX2) at DNFA41 locus has been reported leading to a bilateral and symmetrical sensorineural non-syndromic autosomal dominant HHL in two Chinese families. We performed a linkage analysis in a large Italian family with a dominant pattern of inheritance showing a significant 3.31 LOD score in a 2Mb region overlapping with the DNFA41 locus. Molecular analyses of P2RX2 identified a novel missense mutation (p.Gly353Arg) affecting a residue highly conserved across species. Visual inspection of the protein structure as obtained from comparative modeling suggests that substitution of the small glycine residue with a charged bulky residue such as an arginine that is close to the 'neck' of the region responsible for ion channel gating should have a high energetic cost and should lead to a severely destabilization of the fold. The identification of a second most likely causative mutation in P2RX2 gene further supports the possible role of this gene in causing autosomal dominant HHL
Lifestyle and normal hearing function in Italy and Central Asia: The potential role of coffee
No full textBackground: Sound perception has a fundamental role of the auditory system and its absence causes hearing loss. It is
well known that normal hearing function as well as the non-Mendelian forms of hearing impairment (i.e. age-related
and noise-induced hearing loss) are considered to be due to both genetic and lifestyle/environmental factors. To date,
few factors have been hypothesized as being related to normal hearing function and to age-related and noise-induced
hearing loss. Method: We describe a broad study carried out on 4401 subjects from isolated populations (located from
Italy to Central Asia) aimed at the identifi cation of lifestyle/environmental factors (focused mainly on diet) that are
potentially associated with normal hearing function (i.e. quantitative trait). Results: Our results show, for the fi rst time,
that among eight analysed variables (smoking, chocolate, coffee, tea, wine, beer, dairy products, spirits), only coffee
consumption and coffee intake showed a signifi cant association with better hearing function in four out of the 11 countries
investigated. In particular, coffee consumption was associated over an audiometric profi le from low (250, 500, 1000
Hz) to high (4000, 8000 Hz) frequencies: p -value 0.006 in southern Italy, p -value 0.017 in Azerbaijan, p -value 0.016
in Tajikistan at low frequencies and p -value 0.038 in Sardinia at high frequencies. With regard to intake, we detected
an association only at high frequencies (2 cups/day, p -value 0.01; 3 cups/day, p -value 0.003). Conclusion: A possible
explanation might be the antioxidant content of coffee, the concentration of which is higher than red wine or herbal
teas. A possible additional reason could be a specifi c protective effect of active coffee compounds such as trigonelline.
The fi ndings provide a better knowledge of environment/lifestyle factors related to the hearing system and might help
in defi ning new preventive strategies for hearing loss
Age-related hearing loss and level of education: an epidemiological study on a large cohort of isolated popu-lations
No full textAbstract
Objective: Age related hearing loss (ARHL) or presbyacusis is a complex condition caused by an interaction between
environmental and genetic factors and is the most prevalent sensory impairment in the elderly. To date, only few
environmental/lifestyle risk factors have been found. Research into risk factors underlying ARHL is increasingly urgent
as populations grow older. Here, we investigate the relationship between ARHL and educational/occupational factors in
a large cohort of people from isolated villages in Italy, Crimea region, Caucasus and Central Asia. Methods: Two thousand
and sixty-eight people (aged 40 – 95 years) were recruited and analysed. Education was classified at fi ve levels: no education,
elementary, secondary, high school and university. Cases and controls were defined after a detailed evaluation of the
hearing phenotype. Data were analysed using a mixed-effects logistic regression. Results: A statistically significant association
between ARHL and education was detected. People with no education showed a higher association with the condition
than people with a higher education ( p < 0.001). Explanations could be many, including individual jobs. A strong correlation
( φ >0.45) between occupation and level of education was also found. Conclusion: Present findings provide a better
knowledge of environment/lifestyle factors related to ARHL and might help in defining new preventive strategies for aging
people
Increased rate of deleterious variants in long runs of homozygosity of an inbred population from Qatar
No full textOBJECTIVE:
The aim of this study is to evaluate the fraction of putatively deleterious variants within genomic runs of homozygosity (ROH) regions in an inbred and selected cohort of Qatari individuals.
METHODS:
High-density SNP array analysis was performed in 36 individuals, and for 14 of them whole-exome sequencing (WES) was also carried out.
RESULTS:
In all individuals, regions characterized by a high (hotspot) or low (coldspot) degree of homozygosity in all the analysed individuals were mapped, and the most frequent hotspot regions were selected. WES data were exploited to identify the single nucleotide variations (SNVs) harboured by genes located within both regions in each individual. Evolutionary conservation-based algorithms were employed to predict the potential deleteriousness of SNVs. The amount of in silico predicted deleterious SNVs was significantly different (p < 0.05) between homozygosity hotspot and coldspot regions.
CONCLUSION:
Genes located within ROH hotspot regions contain a significant burden of predicted putatively deleterious variants compared to genes located outside these regions, suggesting inbreeding as a possible mechanism allowing an enrichment of putatively deleterious variants at the homozygous state
Frequency of hearing loss in a series of rural communities of five developing countries located along the Silk Road
No full textHearing loss (HL) affects millions of people worldwide. While epidemiological data from Western countries are already available, this information is still lacking for many developing countries and rural communities. Here we report, for the first time, a study on the frequency of HL in a series of rural communities located along the Silk Road. Study design: Four hundred and ninety-six subjects (236 males and 260 females ranging from eight to 84 years of age) selected in non-random, convenience samples from rural communities belonging to Terra Madre Organization have been enrolled: 228 from Georgia and Azerbaijan (Caucasus region), 151 from Uzbekistan and Kazakhstan (Central Asia), and 117 from Pair (Tajikistan). Subjects underwent pure-tone audiometry at 0.25, 0.5, 1, 2, 4, 6, and 8 kHz; pure-tone average (PTA) values were determined. Results: The overall HL frequency, ranging from 9% to 18%, in the investigated communities located along the Silk Road is higher than that reported for WHO European region countries but comparable with that reported for WHO South-East Asian region countries and other developing countries. Interestingly, with regard to the impact of age, two different disease behaviours have been identified in all the tested communities – one for males and the other for females. In females HL starts at all PTAs between 30 and 40 years of age. In contrast, in males age starts to affect hearing at high frequencies in young adulthood (20–25 years old), but later (50–60 years old) at low and medium frequencies. Conclusion: Despite the difficulty in reaching rural communities, mainly located in remote places, and the need to perform further studies using a larger sample size, recent data provide new information and will contribute to a better definition of HL worldwide frequency
Novel genetic determinants contribute to hearing loss in a central European cohort with enlarged vestibular aqueduct /
Full text linkBackground: The enlarged vestibular aqueduct (EVA) is the most commonly detected inner ear malformation. Biallelic pathogenic variants in the SLC26A4 gene, coding for the anion exchanger pendrin, are frequently involved in determining Pendred syndrome and nonsyndromic autosomal recessive hearing loss DFNB4 in EVA patients. In Caucasian cohorts, the genetic determinants of EVA remain unknown in approximately 50% of cases. We have recruited a cohort of 32 Austrian patients with hearing loss and EVA to define the prevalence and type of pathogenic sequence alterations in SLC26A4 and discover novel EVA-associated genes. Methods: Sanger sequencing, single nucleotide polymorphism (SNP) assays, copy number variation (CNV) testing, and Exome Sequencing (ES) were employed for gene analysis. Cell-based functional and molecular assays were used to discriminate between gene variants with and without impact on protein function. Results: SLC26A4 biallelic variants were detected in 5/32 patients (16%) and monoallelic variants in 5/32 patients (16%). The pathogenicity of the uncharacterized SLC26A4 protein variants was assigned or excluded based on their ion transport function and cellular abundance. The monoallelic or biallelic Caucasian EVA haplotype was detected in 7/32 (22%) patients, but its pathogenicity could not be confirmed. X-linked pathogenic variants in POU3F4 (2/32, 6%) and biallelic pathogenic variants in GJB2 (2/32, 6%) were also found. No CNV of SLC26A4 and STRC genes was detected. ES of eleven undiagnosed patients with bilateral EVA detected rare sequence variants in six EVA-unrelated genes (monoallelic variants in SCD5, REST, EDNRB, TJP2, TMC1, and two variants in CDH23) in five patients (5/11, 45%). Cell-based assays showed that the TJP2 variant leads to a mislocalized protein product forming dimers with the wild-type, supporting autosomal dominant pathogenicity. The genetic causes of hearing loss and EVA remained unidentified in (14/32) 44% of patients. Conclusions: The present investigation confirms the role of SLC26A4 in determining hearing loss with EVA, identifies novel genes in this pathophysiological context, highlights the importance of functional testing to exclude or assign pathogenicity of a given gene variant, proposes a possible diagnostic workflow, suggests a novel pathomechanism of disease for TJP2, and highlights voids of knowledge that deserve further investigation
Going Beyond Counting First Authors in Author Co-citation Analysis
Full text linkThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Identifying missing pieces in color vision defects: a genome-wide association study in Silk Road populations
Full text linkIntroduction: 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 (OPN1LW, OPN1MW, OPN1SW) or as a combination of genetic predisposition and environmental factors. To date, apart from Mendelian CVDs forms, nothing is known about multifactorial CVDs forms. Materials and Methods: 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. Results: Concerning DP, three genes: PIWIL4 (FDR-p: 9.01*10-9), MBD2 (FDR-p: 4.97*10-8) and NTN1 (FDR-p: 4.98*10-8), stood out as promising candidates. PIWIL4 is involved in the preservation of Retinal Pigmented Epithelium (RPE) homeostasis while MBD2 and NTN1 are both involved in visual signal transmission. With regards to TR, four genes: VPS54 (FDR-p: 4.09*10-9), IQGAP (FDR-p: 6,52*10-10), NMB (FDR-p: 8.34*10-11), and MC5R (FDR-p: 2.10*10-8), were considered promising candidates. VPS54 is reported to be associated with Retinitis pigmentosa; IQGAP1 is reported to regulate choroidal vascularization in Age-Related Macular Degeneration; NMB is involved in RPE homeostasis regulation; MC5R is reported to regulate lacrimal gland function. Discussion: Overall, these results provide novel insights regarding a complex phenotype (i.e., CVDs) in an underrepresented population such as Silk Road isolated communities
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