A variant in a transcription factor gene, POU4F3, is responsible for autosomal dominant nonsyndromic hereditary hearing loss, DFNA15. To date, 14 variants, including a whole deletion of POU4F3, have ...been reported to cause HL in various ethnic groups. In the present study, genetic screening for POU4F3 variants was carried out for a large series of Japanese hearing loss (HL) patients to clarify the prevalence and clinical characteristics of DFNA15 in the Japanese population. Massively parallel DNA sequencing of 68 target candidate genes was utilized in 2,549 unrelated Japanese HL patients (probands) to identify genomic variations responsible for HL. The detailed clinical features in patients with POU4F3 variants were collected from medical charts and analyzed. Novel 12 POU4F3 likely pathogenic variants (six missense variants, three frameshift variants, and three nonsense variants) were successfully identified in 15 probands (2.5%) among 602 families exhibiting autosomal dominant HL, whereas no variants were detected in the other 1,947 probands with autosomal recessive or inheritance pattern unknown HL. To obtain the audiovestibular configuration of the patients harboring POU4F3 variants, we collected audiograms and vestibular symptoms of the probands and their affected family members. Audiovestibular phenotypes in a total of 24 individuals from the 15 families possessing variants were characterized by progressive HL, with a large variation in the onset age and severity with or without vestibular symptoms observed. Pure-tone audiograms indicated the most prevalent configuration as mid-frequency HL type followed by high-frequency HL type, with asymmetry observed in approximately 20% of affected individuals. Analysis of the relationship between age and pure-tone average suggested that individuals with truncating variants showed earlier onset and slower progression of HL than did those with non-truncating variants. The present study showed that variants in POU4F3 were a common cause of autosomal dominant HL.
More than 400 syndromes associated with hearing loss and other symptoms have been described, corresponding to 30% of cases of hereditary hearing loss. In this study we aimed to clarify the mutation ...spectrum of syndromic hearing loss patients in Japan by using next-generation sequencing analysis with a multiple syndromic targeted resequencing panel (36 target genes). We analyzed single nucleotide variants, small insertions, deletions and copy number variations in the target genes. We enrolled 140 patients with any of 14 syndromes (BOR syndrome, Waardenburg syndrome, osteogenesis imperfecta, spondyloepiphyseal dysplasia congenita, Stickler syndrome, CHARGE syndrome, Jervell and Lange-Nielsen syndrome, Pendred syndrome, Klippel-Feil syndrome, Alport syndrome, Norrie disease, Treacher-Collins syndrome, Perrault syndrome and auditory neuropathy with optic atrophy) and identified the causative variants in 56% of the patients. This analysis could identify the causative variants in syndromic hearing loss patients in a short time with a high diagnostic rate. In addition, it was useful for the analysis of the cases who only partially fulfilled the diagnostic criteria.
Dynamic viscoelastic properties and stress relaxation behavior of column-fractionated high density polyethylene melts are studied. Effects of long branching on the rheo-logical properties are ...investigated for fractions obtained from two types of whole polymers which are produced using different kind of catalysts. The following conclusions are obtained from the measurements on fraction samples with and without long branches. Fractions including polymer chains with long branches have relaxation mechanism with long relaxation times due to their branched structure. It is found that long branching produces strong effects on viscosity and compliance in the terminal region: Zero-shear viscosity η0, shows stronger dependence on molecular weight Mw than the usual power-low dependence. Steady state compliance Je0 exhibits unusually strong dependence on molecular weight distribution.This apparent strong-dependence is attributed to the molecular weight dependence of Je0 in the branched samples. From stress relaxation experiments, it is found that effects of long branching and molecular weight distribution on the damping function h(γ) are minor in high density polyethylene melts.
Shear and elongational flow properties of high density polyethylene melts are studied. Effects of long branching and molecular weight distribution on rheological properties are investigated for two ...types of samples, which are produced using different kind of catalysts. The following conclusions are obtained. (1) Contribution of a relaxation mechanism with very long relaxation times due to the long branch of the sample appears in dynamic viscoelastic functions, relaxation modulus and in elongational viscosity. (2) Difference in shear flow properties between two types of samples is marked in the region corresponding to much lower stress level than that met in the measurement of melt flow rate. (3) The strain dependence of damping function obtained in stress relaxation measurement is similar to each other for two types of samples. (4) Sharp upturn of elongational viscosity is observed for two samples; one with long branch (es) and other with (possibly) extremely high molecular weight tail.
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