Additional heterozygous 2507A>C mutation of WFS1 in progressive hearing loss at lower frequencies

Objectives/Hypothesis:

To describe the audiological profiles in a Japanese family with autosomal dominant hereditary sensorineural hearing loss (SNHL) and to identify the causative gene.

Study Design:

A family study at an academic tertiary referral center.

Methods:

A family with autosomal dominant hereditary SNHL was enrolled. Hearing loss (HL) of affected members showed mid‐frequency SNHL in childhood and progressed at lower frequencies with age, resulting in low‐frequency SNHL. To understand the pathology of HL of this family, we performed a genetic analysis of WFS1, TECTA, and GJB2 by direct sequencing, and further audiovestibular examinations, including speech audiometry, distortion product otoacoustic emissions, electrocochleography, auditory brainstem responses, and electronystagmography for some affected members.

Results:

A heterozygous A‐to‐C nucleotide transversion (c.2507A>C), resulting in a lysine‐to‐threonine substitution at codon 836 (K836T) was identified in exon 8 of WFS1. K836T was segregated with HL in the 15 participants in the genetic study but was not detected in the 212 normal chromosomes. Only polymorphic changes were detected in TECTA and GJB2. Audiovestibular examinations indicated purely cochlear HL and normal vestibular function. The summating potential/action potential ratios in electrocochleography increased in the bilateral ears of the proband.

Conclusions:

The family described with autosomal dominant inheritance of K836T of the WFS1 gene demonstrates a progressive hearing loss in the lower frequencies. Laryngoscope, 2010     

Dose and dose-rate effects of X rays and fission neutrons on lymphocyte apoptosis in p53(+/+) and p53(-/-) mice

Following the exposure of mice to X rays or fission neutrons, the frequency (F) of apoptosis was measured after 4 h, and the weight loss or lymphocyte content loss in the thymus and spleen was measured after 24 h. In p53(+/+) mice, F increased linearly with the dose (D (Gy)) and the induced rate per Gy of F (detected by TUNEL staining) was 0.05 and 0.23 for X rays and fission neutrons, respectively. Therefore, the RBE of fission neutrons was 4.6 for apoptosis induction. This indicates that radiation-induced apoptosis is mostly due to double strand breaks (DSBs) in DNA because we previously obtained almost the same RBE value of fission neutrons for the induction of crossover mutations in Drosophila melanogaster, which arise from the recombinational repair of DSBs. In p53(+/+) mice, decreases in the organ weight and the lymphocyte content were observed for the thymus and the spleen 24 h after X-irradiation. These atrophic changes in the thymus and the spleen quantitatively corresponded to the total apoptotic cell deaths occurring in them. However, in p53(-/-) mice, no vigorous apoptosis was induced after X-irradiation, and hyperplastic changes in the weight and the lymphocyte content appeared in the thymus and the spleen 24 h after X-irradiation. In p53(+/+) mice, there was no difference in the induced rate per Gy of reduction in the surviving fraction of lymphocytes between acute (0.4 Gy/min) and chronic (3 mGy/min) gamma-irradiations. Namely, radiation-induced apoptosis in lymphocytes is a dose-rate independent event.     

Tributyltin-induced endoplasmic reticulum stress and its Ca-mediated mechanism

Organotin compounds, especially tributyltin chloride (TBT), have been widely used in antifouling paints for marine vessels, but exhibit various toxicities in mammals. The endoplasmic reticulum (ER) is a multifunctional organelle that controls post-translational modification and intracellular Ca^2 + signaling. When the capacity of the quality control system of ER is exceeded under stress including ER Ca^2 + homeostasis disruption, ER functions are impaired and unfolded proteins are accumulated in ER lumen, which is called ER stress. Here, we examined whether TBT causes ER stress in human neuroblastoma SH-SY5Y cells. We found that 700 nM TBT induced ER stress markers such as CHOP, GRP78, spliced XBP1 mRNA and phosphorylated eIF2α. TBT also decreased the cell viability both concentration- and time-dependently. Dibutyltin and monobutyltin did not induce ER stress markers. We hypothesized that TBT induces ER stress via Ca^2 + depletion, and to test this idea, we examined the effect of TBT on intracellular Ca^2 + concentration using fura-2 AM, a Ca^2 + fluorescent probe. TBT increased intracellular Ca^2 + concentration in a TBT-concentration-dependent manner, and Ca^2 + increase in 700 nM TBT was mainly blocked by 50 μM dantrolene, a ryanodine receptor antagonist (about 70% inhibition). Dantrolene also partially but significantly inhibited TBT-induced GRP78 expression and cell death. These results suggest that TBT increases intracellular Ca^2 + concentration by releasing Ca^2 + from ER, thereby causing ER stress.     

A case of primary extramedullary plasmacytoma in the posterior cervical portion

This case involves a 16-year-old woman with a posterior cervical tumor. Histologically, it was found to be a extramedullary plasmacytoma (EMP). Immunohistochemically, IgG was present in the plasma cells that were shown to be atypia by the PAP method. Laboratory data revealed no other abnormalities. A surgical excision of the tumor was performed with a dissection of the relevant lymph nodes. Although irradiation and chemotherapy were administered postoperatively, multiple bone metastasis was found a month after the operation, and the patient died 8 months later.     

Hypercalcemia in a Case of Childhood Acute Lymphoblastic Leukemia

Severe hypercalcemia (serum calcium, 4.25–5.25 mmol/l),in association with osteolytic bone lesions, was found in agirl aged 2 yr 7 mo with common acute lymphoblastic leukemia(ALL). Hormonal studies excluded the possibility of the hypercalcemiabeing caused by primary hyperparathyroidism or ectopic parathyroidhormone secretion. Increased plasma prostaglandinE₂ (PGE₂).Jlevels (130 ng/l), probably produced by leukemic cells, wereconsidered to be one of the pathogenic mechanisms responsiblefor the occurrence of hypercalcemia in this patient. Both thehypercalcemia and the abnormal plasma PGE₂ level returned tonormal after chemotherapy.