1,721,066 research outputs found
A new locus (DFNA47) for autosomal dominant non-syndromic inherited hearing loss maps to 9p21-22 in a large Italian family.
No full textA 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
Charcot-Marie-Tooth disease type 2C: a distinct genetic entity. Clinical and molecular characterization of the first European family.
No full textCharcot- Marie-Tooth disease type 2 is clinically and genetically heterogeneous. A particular clinical subtype of autosomal dominant Charcot-Marie-Tooth disease type 2, characterized by diaphragm and vocal cord paralysis, is labelled Charcot-Marie-Tooth disease type 2C but no genetic locus has been mapped for this form. We describe the first European family affected by Charcot-Marie-Tooth disease type 2C. Genetic analysis excluded linkage to locus of Charcot-Marie-Tooth disease type 2A, B, D, E and F, and to locus of distal hereditary motor neuronopathy type VII. In this family the disease has high penetrance, variable severity and apparently the most severe limb muscle involvement in the youngest generation. Vocal cord paralysis is unrelated to the degree of muscular weakness and patients with the most severe muscle involvement have absent or minimal respiratory symptoms. Charcot-Marie-Tooth disease type 2C is clinically and genetically different from Charcot-Marie-Tooth disease type 2A, B, D, E and F, and is not allelic with distal hereditary motor neuronopathy type VII
A Novel CRYBB2 Missense Mutation Causing Congenital Autosomal Dominant Cataract in an Italian Family.
No full textCongenital cataract is a leading cause of visual impairment in children and brings approximately 10% of childhood blindness worldwide. Molecular analysis revealed ~60 loci to be associated with several phenotypes of childhood cataracts. Until now, more than 30 loci and 18 genes on different chromosomes have been associated with autosomal dominant congenital cataract (ADCC). Here, we present a three-generation Italian family with a non syndromic ADCC. A linkage analysis carried out using HumanCytoSNP-12 DNA Analysis BeadChip led us to identify ten genomic regions virtually involved in the disease. All the genes located in these regions were scored for possible relationship with ADCC and, according to a strict clinical and genetic selection, 4 genes have been analyzed. A novel sequence variant was found in the CRYBB2 gene (p.Ser143Phe). This variant affects a conserved aminoacid in the third Greek key motif of the protein, cosegregates with the disease phenotype in all affected individuals and is not present both in the unaffected family members and 100 healthy control subjects. Finally, we identified the first CRYBB2 mutation in an Italian family causing a clinical picture of ADCC
Genetic variation in taste sensitivity to 6-n-propylthiouracil and its relationship to taste perception and food selection.
No full textThe ability to taste bitter thiourea compounds and related chemicals is a well-known human trait. The majority of individuals perceive these compounds, typified by the bitterness of 6-n-propylthiouracil (PROP) and phenylthiocarbamide (PTC), as moderately-to-extremely bitter. Approximately 30\% of the population is taste blind to these substances. It has been hypothesized that PROP/PTC tasters are more sensitive to other bitter tastes, sweet taste, the pungency of chili peppers, the astringency of alcohol, and the texture of fats. Tasters may also show lower preferences for foods with these taste qualities than nontasters who show the opposite set of responses (i.e., lower taste sensitivities and higher preferences for these sensory qualities). This pathway is illustrated in the following model: PROP Sensitivity --> Food Perception -->Preference --> Selection. Robust associations between PROP status and taste perceptions have been well documented. However, subsequent links to food preferences and diet selection have been more difficult to demonstrate. This is not surprising given the complexity of human ingestive behavior that is influenced by numerous factors including health attitudes, personality traits, and cultural norms. Our laboratory has been using PROP screening to investigate individual differences in the selection of bitter foods, especially bitter tasting vegetables and fruits that may have long-term health implications. This chapter will discuss new and recent findings addressing the following issues: 1) whether PROP-related differences in perception of bitter compounds predict the perception and liking of bitter foods; 2) the role of bitter taste modifiers; and 3) the influence of personal characteristics such as food attitudes and cultural background on PROP-related food preferences
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
Autosomal recessive stickler syndrome due to a loss of function mutation in theCOL9A3gene
No full textStickler syndrome (STL) is a clinically variable and genetically heterogeneous syndrome characterized by ophthalmic, articular, orofacial, and auditory manifestations. STL has been described with both autosomal dominant and recessive inheritance. The dominant form is caused by mutations of COL2A1 (STL 1, OMIM 108300), COL11A1 (STL 2, OMIM 604841), and COL11A2 (STL 3, OMIM 184840) genes, while recessive forms have been associated with mutations of COL9A1 (OMIM 120210) and COL9A2 (OMIM 120260) genes. Type IX collagen is a heterotrimeric molecule formed by three genetically distinct chains: α1, α2, and α3 encoded by the COL9A1, COL9A2, and COL9A3 genes. Up to this time, only heterozygous mutations of COL9A3 gene have been reported in human and related to: (1) multiple epiphyseal dysplasia type 3, (2) susceptibility to an intervertebral disc disease, and (3) hearing loss. Here, we describe the first autosomal recessive Stickler family due to loss of function mutations (c.1176_1198del, p.Gln393Cysfs*25) of COL9A3 gene. These findings extend further the role of collagen genes family in the disease pathogenesis
Genomic instability in congenital lung malformations in children
No full textPurpose: To study the biological relationship between congenital lung malformations (CLMs) and malignancy. Methods: Biopsies of 12 CPAMs, 6 intralobar sequestrations and 2 extralobar sequestrations were analyzed through whole-genome sequencing. Blood samples from 10 patients were used to confirm or exclude somatic mosaicism. Putative somatic Single Nucleotide Variants (SNVs) were called for each malformed sample with a Panel of Normals built with control DNA samples extracted from blood. The variants were subsequently confirmed by Sanger sequencing and searched, whenever possible, in the blood samples of patients. Results: All CLMs but one presented a signature of genomic instability by means of multiple clusters of cells with gene mutations. Seven tumor transformation-related SNVs were detected in 6/20 congenital lung malformations. Four very rare in the general population SNVs were found in a region previously linked to lung cancer in 5p15.33, upstream of TERT oncogene. Furthermore, we identified missense genetic variants, whose tumorigenic role is well known, in the RET, FANCA and MET genes. Conclusions: Genomic instability in 95% of CLMs and genetic variants linked to tumor development in 30% of them, regardless of histopathology, are predisposing factors to malignancy, that combined with exposure to carcinogens, might trigger the development of malignancy and explain the association between CLMs and lung cancer
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