Expression pattern of the mouse ortholog of the Pendred's syndrome gene (Pds) suggests a key role for pendrin in the inner ear.
(17/1607)
Pendred's syndrome is an autosomal-recessive disorder characterized by deafness and goiter. After our recent identification of the human gene mutated in Pendred's syndrome (PDS), we sought to investigate in greater detail the expression of the gene and the function of its encoded protein (pendrin). Toward that end, we isolated the corresponding mouse ortholog (Pds) and performed RNA in situ hybridization on mouse inner ears (from 8 days postcoitum to postnatal day 5) to establish the expression pattern of Pds in the developing auditory and vestibular systems. Pds expression was detected throughout the endolymphatic duct and sac, in distinct areas of the utricle and saccule, and in the external sulcus region within the cochlea. This highly discrete expression pattern is unlike that of any other known gene and involves several regions thought to be important for endolymphatic fluid resorption in the inner ear, consistent with the putative functioning of pendrin as an anion transporter. These studies provide key first steps toward defining the precise role of pendrin in inner ear development and elucidating the pathogenic mechanism for the deafness seen in Pendred's syndrome. (+info)
Altered cochlear fibrocytes in a mouse model of DFN3 nonsyndromic deafness.
(18/1607)
DFN3, an X chromosome-linked nonsyndromic mixed deafness, is caused by mutations in the BRN-4 gene, which encodes a POU transcription factor. Brn-4-deficient mice were created and found to exhibit profound deafness. No gross morphological changes were observed in the conductive ossicles or cochlea, although there was a dramatic reduction in endocochlear potential. Electron microscopy revealed severe ultrastructural alterations in cochlear spiral ligament fibrocytes. The findings suggest that these fibrocytes, which are mesenchymal in origin and for which a role in potassium ion homeostasis has been postulated, may play a critical role in auditory function. (+info)
Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome.
(19/1607)
BACKGROUND: We have sought to establish the prevalence of goitre within a Pendred syndrome (PS) cohort and to document the course of thyroid disease in this patient group. As part of a genetic study of PS we have assessed 57 subjects by perchlorate discharge test and in 52 (M 21, F 31, age range 9-54 years) a discharge of radioiodide of >10% was observed. RESULTS: Goitre was present in 43 (83%) of the cohort (28 F, 15 M), generally developing after the age of 10 years, 56% remained euthyroid (age range 9-37 years), and 19 patients (44%) had objective evidence of hypothyroidism, all of whom had goitre. CONCLUSIONS: In summary, thyroid dysfunction in PS is variable and inclusion of goitre as a diagnostic requirement will maintain significant underascertainment. The recent identification of the genetic defect underlying PS is likely to provide an important diagnostic aid in the identification of this disorder and this communication should assist clinicians in identifying deaf patients who ought to be considered for this investigation. (+info)
Mice lacking the basolateral Na-K-2Cl cotransporter have impaired epithelial chloride secretion and are profoundly deaf.
(20/1607)
In chloride-secretory epithelia, the basolateral Na-K-2Cl cotransporter (NKCC1) is thought to play a major role in transepithelial Cl(-) and fluid transport. Similarly, in marginal cells of the inner ear, NKCC1 has been proposed as a component of the entry pathway for K(+) that is secreted into the endolymph, thus playing a critical role in hearing. To test these hypotheses, we generated and analyzed an NKCC1-deficient mouse. Homozygous mutant (Nkcc1(-/-)) mice exhibited growth retardation, a 28% incidence of death around the time of weaning, and mild difficulties in maintaining their balance. Mean arterial blood pressure was significantly reduced in both heterozygous and homozygous mutants, indicating an important function for NKCC1 in the maintenance of blood pressure. cAMP-induced short circuit currents, which are dependent on the CFTR Cl(-) channel, were reduced in jejunum, cecum, and trachea of Nkcc1(-/-) mice, indicating that NKCC1 contributes to cAMP-induced Cl(-) secretion. In contrast, secretion of gastric acid in adult Nkcc1(-/-) stomachs and enterotoxin-stimulated fluid secretion in the intestine of suckling Nkcc1(-/-) mice were normal. Finally, homozygous mutants were deaf, and histological analysis of the inner ear revealed a collapse of the membranous labyrinth, consistent with a critical role for NKCC1 in transepithelial K(+) movements involved in generation of the K(+)-rich endolymph and the endocochlear potential. (+info)
Recruitment of the auditory cortex in congenitally deaf cats by long-term cochlear electrostimulation.
(21/1607)
In congenitally deaf cats, the central auditory system is deprived of acoustic input because of degeneration of the organ of Corti before the onset of hearing. Primary auditory afferents survive and can be stimulated electrically. By means of an intracochlear implant and an accompanying sound processor, congenitally deaf kittens were exposed to sounds and conditioned to respond to tones. After months of exposure to meaningful stimuli, the cortical activity in chronically implanted cats produced field potentials of higher amplitudes, expanded in area, developed long latency responses indicative of intracortical information processing, and showed more synaptic efficacy than in naive, unstimulated deaf cats. The activity established by auditory experience resembles activity in hearing animals. (+info)
Response of inferior colliculus neurons to electrical stimulation of the auditory nerve in neonatally deafened cats.
(22/1607)
Response properties of neurons in the inferior colliculus (IC) were examined in control and profoundly deafened animals to electrical stimulation of the auditory nerve. Seven adult cats were used: two controls; four neonatally deafened (2 bilaterally, 2 unilaterally); and one long-term bilaterally deaf cat. All control cochleae were deafened immediately before recording to avoid electrophonic activation of hair cells. Histological analysis of neonatally deafened cochleae showed no evidence of hair cells and a moderate to severe spiral ganglion cell loss, whereas the long-term deaf animal had only 1-2% ganglion cell survival. Under barbiturate anesthesia, scala tympani electrodes were implanted bilaterally and the auditory nerve electrically stimulated using 100 micros/phase biphasic current pulses. Single-unit (n = 419) recordings were made through the lateral (LN) and central (ICC) nuclei of the IC; responses could be elicited readily in all animals. Approximately 80% of cells responded to contralateral stimulation, whereas nearly 75% showed an excitatory response to ipsilateral stimulation. Most units showed a monotonic increase in spike probability and reduction in latency and jitter with increasing current. Nonmonotonic activity was seen in 15% of units regardless of hearing status. Neurons in the LN exhibited longer latencies (10-25 ms) compared with those in the ICC (5-8 ms). There was a deafness-induced increase in latency, jitter, and dynamic range; the extent of these changes was related to duration of deafness. The ICC maintained a rudimentary cochleotopic organization in all neonatally deafened animals, suggesting that this organization is laid down during development in the absence of normal afferent input. Temporal resolution of IC neurons was reduced significantly in neonatal bilaterally deafened animals compared with acutely deafened controls, whereas neonatal unilaterally deafened animals showed no reduction. It would appear that monaural afferent input is sufficient to maintain normal levels of temporal resolution in auditory midbrain neurons. These experiments have shown that many of the basic response properties are similar across animals with a wide range of auditory experience. However, important differences were identified, including increased response latencies and temporal jitter, and reduced levels of temporal resolution. (+info)
Genetic linkage of the Muckle-Wells syndrome to chromosome 1q44.
(23/1607)
The Muckle-Wells syndrome (MWS) is a hereditary inflammatory disorder characterized by acute febrile inflammatory episodes comprising abdominal pain, arthritis, and urticaria. Progressive nerve deafness develops subsequently, and, after several years, the disease is complicated by multiorgan AA-type amyloidosis (i.e., amyloidosis derived from the inflammatory serum amyloid-associated protein) (MIM 191900) with renal involvement and end-stage renal failure. The mode of inheritance is autosomal dominant, but some sporadic cases have also been described. No specific laboratory findings have been reported. The genetic basis of MWS is unknown. Using a genomewide search strategy in three families, we identified the locus responsible for MWS, at chromosome 1q44. Our results indicate that the gene is located within a 13.9-cM region between markers D1S2811 and D1S2882, with a maximum two-point LOD score of 4. 66 (recombination fraction.00) at D1S2836 when full penetrance is assumed. Further identification of the specific gene that is responsible for MWS will therefore provide the first biological element for characterizing MWS, other than doing so on the basis of its variable clinical expression. (+info)
Cochlear implantations in Northern Ireland: an overview of the first five years.
(24/1607)
During the last few years cochlear implantation (CI) has made remarkable progress, developing from a mere research tool to a viable clinical application. The Centre for CI in the Northern Ireland was established in 1992 and has since been a provider of this new technology for rehabilitation of profoundly deaf patients in the region. Although individual performance with a cochlear implant cannot be predicted accurately, the overall success of CI can no longer be denied. Seventy one patients, 37 adults and 34 children, have received implants over the first five years of the Northern Ireland cochlear implant programme, which is located at the Belfast City Hospital. The complication rates and the post-implantation outcome of this centre compare favourably with other major centres which undertake the procedure. This paper aims to highlight the patient selection criteria, surgery, post-CI outcome, clinical and research developments within our centre, and future prospects of this recent modality of treatment. (+info)