Controversies in aural atresia repair.

Purpose Of Review: To discuss recent controversies regarding the management of aural atresia.

Recent Findings: Management of unilateral atresia is less controversial. Candidacy for successful repair is based on high-resolution computed tomography findings and atresia grading.

Coexistence of mitochondrial 12S rRNA C1494T and CO1/tRNA(Ser(UCN)) G7444A mutations in two Han Chinese pedigrees with aminoglycoside-induced and non-syndromic hearing loss.

Mutations in mitochondrial DNA are one of the important causes of hearing loss. We report here the clinical, genetic, and molecular characterization of two Han Chinese pedigrees with maternally transmitted aminoglycoside-induced and nonsyndromic bilateral hearing loss. Clinical evaluation revealed the wide range of severity, age-at-onset, and audiometric configuration of hearing impairment in matrilineal relatives in these families.

Human TRMU encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase is a putative nuclear modifier gene for the phenotypic expression of the deafness-associated 12S rRNA mutations.

Nuclear modifier genes have been proposed to modulate the phenotypic manifestation of human mitochondrial 12S rRNA A1491G mutation associated with deafness in many families world-wide. Here we identified and characterized the putative nuclear modifier gene TRMU encoding a highly conserved mitochondrial protein related to tRNA modification. A 1937bp TRMU cDNA has been isolated and the genomic organization of TRMU has been elucidated.

Molecular mechanisms underlying inner ear patterning defects in kreisler mutants.

Prior studies have shown that kreisler mutants display early inner ear defects that are related to abnormal hindbrain development and signaling. These defects in kreisler mice have been linked to mutation of the kr/mafB gene. To investigate potential relevance of kr/mafB and abnormal hindbrain development in inner ear patterning, we analyzed the ear morphogenesis in kreisler mice using a paint-fill technique.

Improved diagnostic effectiveness with a sequential diagnostic paradigm in idiopathic pediatric sensorineural hearing loss.

Objectives: To determine whether a stepwise diagnostic paradigm is more diagnostically efficient and cost-effective than a simultaneous testing approach in the evaluation of idiopathic pediatric sensorineural hearing loss (SNHL).

Design: Prospective prevalence study.

Setting: Tertiary referral children's hospital.

Mutations in MTO2 related to tRNA modification impair mitochondrial gene expression and protein synthesis in the presence of a paromomycin resistance mutation in mitochondrial 15 S rRNA.

Nuclear gene(s) have been shown to modulate the phenotypic expression of mitochondrial DNA mutations. We report here the identification and characterization of the yeast nuclear gene MTO2 encoding an evolutionarily conserved protein involved in mitochondrial tRNA modification. Interestingly, mto2 null mutants expressed a respiratory-deficient phenotype when coexisting with the C1409G mutation of mitochondrial 15 S rRNA at the very conservative site for human deafness-associated 12 S rRNA A1491G and C1409T mutations.

Functional characterization of the mitochondrial 12S rRNA C1494T mutation associated with aminoglycoside-induced and non-syndromic hearing loss.

In this study, we report the biochemical characterization of the deafness-associated mitochondrial 12S rRNA C1494T mutation using 27 cybrid cell lines constructed by transferring mitochondria from 9 lymphoblastoid cell lines derived from a Chinese family into human mitochondrial DNA (mtDNA)-less (rho degrees) cells. Six cybrids derived from two asymptomatic members, and nine cybrids derived from three symptomatic members of the Chinese family carrying the C1494T mutation exhibited approximately 38 and 43% decrease in the rate of mitochondrial protein labeling, respectively, compared with twelve cybrids derived from four Chinese control individuals. These defects are apparently a primary contributor to significant reductions in the rate of overall respiratory capacity or the rate of malate/glutamate promoted respiration, or succinate/G3P-promoted respiration, or TMPD/ascorbate-promoted respiration in mutant cybrid cell lines derived from either symptomatic or asymptomatic individuals.

Biochemical characterization of the deafness-associated mitochondrial tRNASer(UCN) A7445G mutation in osteosarcoma cell cybrids.

The deafness-associated A7445G mutation in the precursor of mitochondrial tRNA(Ser(UCN)) has been identified in several pedigrees from different ethnic backgrounds. To determine the role of nuclear background in the biochemical manifestation associated with the A7445G mutation, we performed a biochemical characterization of this mutation using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from a New Zealand family into human osteosarcoma mtDNA-less (rho(0)) cells. Compared with three control cybrids, three cybrids derived from an affected matrilineal relative carrying the homoplasmic A7445G mutation exhibited approximately 38-57% decrease in the steady-state level of tRNA(Ser(UCN)), which is less reduced levels than in lymphoblastoid cells in the previous study.

Maternally inherited nonsyndromic hearing loss is associated with the T7511C mutation in the mitochondrial tRNASerUCN gene in a Japanese family.

We report here the characterization of a Japanese family with maternally transmitted nonsyndromic hearing loss. Fourteen of 21 matrilineal relatives in this family exhibited early or late-onset/progressive but noncongenital hearing impairment with a wide range of severity, ranging from severe to normal hearing. The age-of-onset varies from 3 to 30 years.

A diagnostic paradigm for childhood idiopathic sensorineural hearing loss.

Objective: Our objective was to determine the diagnostic yield of laboratory testing, radiological imaging, and GJB2 mutation screening in a large cohort of patients with differing severities of idiopathic sensorineural hearing loss (SNHL).

Design And Setting: We undertook a retrospective study of patients presenting with SNHL at our institution from 1993 to 2002.

Results: Laboratory testing had an extremely low yield.

Co-expression of pendrin, vacuolar H+-ATPase alpha4-subunit and carbonic anhydrase II in epithelial cells of the murine endolymphatic sac.

The endolymph in the endolymphatic sac (ES) is acidic (pH 6.6-7). Maintaining this acidic lumen is believed to be important for the normal function of the ES.

Refining the DFNB17 interval in consanguineous Indian families.

We previously mapped the DFNB17 locus to a 3-4 cM interval on human chromosome 7q31 in a large consanguineous Indian family with congenital profound sensorineural hearing loss. To further refine this interval, 30 new highly polymorphic markers and 8 SNPs were analyzed against the pedigree. Re-analysis in the original DFNB 17 family and additional data from a second unrelated consanguineous family with congenital deafness found to map to the interval, limited the area of shared homozygosity-by-descent (HBD) to approximately 4 megabase (Mb) between markers D7S2453 and D7S525.

Genomic organization and expression analysis of the murine Fam3c gene.

Previously, we identified FAM3C as a candidate gene for autosomal recessive nonsyndromic hearing loss locus 17 (DFNB17). This gene has since been found to be a member of a cytokine-like gene family, but its function has not been determined. The purpose of this study was thus to elucidate the gene structure and pattern of expression, providing information that might allow a hypothesis to be developed about FAM3C function of in the inner ear.

Genomic organization, expression, and subcellular localization of mouse mitochondrial seryl-tRNA synthetase.

We report here the identification and characterization of the mouse mitochondrial seryl-tRNA synthetase (mtSerRS). The genomic organization of mouse mtSerRS has been elucidated. The mouse mtSerRS gene containing 16 exons encodes a 519 residue protein with a strong homology to the mitochondria-like seryl-tRNA synthetase of bacteria, yeast, and other homologs.

Biochemical characterization of the mitochondrial tRNASer(UCN) T7511C mutation associated with nonsyndromic deafness.

We report here the biochemical characterization of the deafness-associated mitochondrial tRNA(Ser(UCN)) T7511C mutation, in conjunction with homoplasmic ND1 T3308C and tRNA(Ala) T5655C mutations using cybrids constructed by transferring mitochondria from lymphoblastoid cell lines derived from an African family into human mtDNA-less (rho degrees ) cells. Three cybrids derived from an affected matrilineal relative carrying the homoplasmic T7511C mutation, exhibited approximately 75% decrease in the tRNA(Ser(UCN)) level, compared with three control cybrids. This amount of reduction in the tRNA(Ser(UCN)) level is below a proposed threshold to support a normal rate of mitochondrial protein synthesis in lymphoblastoid cell lines.

Identification and characterization of mouse TRMU gene encoding the mitochondrial 5-methylaminomethyl-2-thiouridylate-methyltransferase.

The nucleotide modification in tRNA plays a pivotal role in the fidelity of translational process. The mutated mitochondrial tRNA (mt tRNA) associated with human diseases often exhibited a defect in nucleotide modification at wobble position of anticodons. Recently, the product of trmU, 5-methylaminomethyl-2-thiouridylate-methyltransferase, has been shown to be one component of enzyme complex for the biosynthesis of mnm5s2U in the wobble position of the bacterial tRNAs.

Cosegregation of C-insertion at position 961 with the A1555G mutation of the mitochondrial 12S rRNA gene in a large Chinese family with maternally inherited hearing loss.

Mutations in the mitochondrial DNA have been shown to be one of the most important causes of sensorineural hearing loss. Here, we report the characterization of a large Chinese family (507 members in six generations) with maternally inherited non-syndromic hearing loss. Members of this family showed variable severity and age-of-onset of hearing impairment.

Maternally inherited aminoglycoside-induced and nonsyndromic deafness is associated with the novel C1494T mutation in the mitochondrial 12S rRNA gene in a large Chinese family.

We report here the characterization of a large Chinese family with maternally transmitted aminoglycoside-induced and nonsyndromic deafness. In the absence of aminoglycosides, some matrilineal relatives in this family exhibited late-onset/progressive deafness, with a wide range of severity and age at onset. Notably, the average age at onset of deafness has changed from 55 years (generation II) to 10 years (generation IV).

Identification and characterization of mouse GTPBP3 gene encoding a mitochondrial GTP-binding protein involved in tRNA modification.

We report here the identification and characterization of mouse GTPBP3 encoding a mitochondrial GTPase. A full-length GTPBP3 cDNA has been isolated and the genomic organization of GTPBP3 has been elucidated. The mouse GTPBP3 gene containing 9 exons encodes a 486 residue protein with a strong homology to the GTPBP3-like proteins of bacteria, yeast, and other homologs, related to tRNA modification.

Expression of aquaporin 1 and 5 in the developing mouse inner ear and audiovestibular assessment of an Aqp5 null mutant.

To examine the potential roles of aquaporins 1 and 5 (AQP1 and AQP5, respectively) in inner ear development and function, we defined their spatial and temporal expression patterns in the developing mouse inner ear and examined the morphologic and physiologic effects of loss of Aqp5 function. Standard in situ hybridization (ISH) and immunohistochemical (IHC) assays were used for expression studies with routine morphologic, behavioral, and physiologic assessments of hearing and balance in Aqp5 null mutant mice. AQP1 was first detected at embryonic day 10.

Genotypic and phenotypic correlations of DFNB1-related hearing impairment in the Midwestern United States.

Objective: To determine the genotypic and phenotypic correlations of hearing impairment (HI) in a midwestern US population related to autosomal recessive nonsyndromic hearing loss locus 1 (DFNB1).

Design: A retrospective review.

Setting: Tertiary care children's hospital.

Mice lacking the B1 subunit of H+ -ATPase have normal hearing.

Acid-base homeostasis of endolymph is thought to be essential for normal inner ear function. This assumption was supported by clinical data from individuals affected by autosomal recessive distal renal tubular acidosis with sensorineural hearing loss. This recessive syndrome was recently demonstrated to be due to mutations in the gene encoding the B1 subunit of H(+)-ATPase (ATP6B1).

A human mitochondrial GTP binding protein related to tRNA modification may modulate phenotypic expression of the deafness-associated mitochondrial 12S rRNA mutation.

Human mitochondrial 12S rRNA A1555G mutation has been found to be associated with deafness. However, putative nuclear modifier gene(s) has been proposed to regulate the phenotypic expression of this mutation. In yeast cells, mutant alleles of MSS1, encoding a mitochondrial GTP-binding protein, manifest a respiratory-deficient phenotype only when coupled with mitochondrial 15S rRNA P(R)(454) mutation corresponding to human A1555G mutation.

Clinical and audiological features in auditory neuropathy.

Objective: To medically and audiologically characterize a population of children diagnosed as having auditory neuropathy (AN).

Study Design: Retrospective medical chart review.

Setting/subjects: We identified 22 patients from a pediatric otology clinic in a tertiary care pediatric hospital setting.

Pediatric cochlear implantation in auditory neuropathy.

Objective: Auditory neuropathy (AN) is characterized by varying degrees of sensorineural hearing loss, an absent or severely abnormal auditory brainstem response, and normal otoacoustic emissions. The nomenclature for this condition reflects the concept that the site of lesion is proximal to the cochlea (e.g.