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Auditory and vestibular phenotypes associated with GATA3 mutation.

ABSTRACT: OBJECTIVE:To report the auditory and vestibular phenotypes of patients with GATA3 mutation. STUDY DESIGN:Case series of 6 patients. SETTING:Tertiary referral center. PATIENTS:All patients had the classic triad of GATA3 deficiency: hypoparathyroidism, hearing loss, and renal dysplasia. Patients (29-60 yr old; mean age, 42.5 yr; 3 male and 3 female subjects) were confirmed to have heterozygous mutations involving GATA3 by Sanger sequencing. INTERVENTIONS:Behavioral audiometry, distortion product otoacoustic emissions (DPOAEs), and auditory brainstem responses (ABRs) were used to assess hearing. Rotational vestibular testing was used to assess vestibular function. RESULTS:All patients with GATA3 mutation presented with hearing loss during childhood. The mean 3-frequency (0.5/1/2 kHz) pure tone average was 67 dB HL (range, 50-83 dB HL; SD, 9.3). The average speech discrimination score was 73% (range, 36%-100%; SD, 15.9). DPOAEs were absent in all patients. ABRs were remarkably robust and provided no evidence of retrocochlear dysfunction. Some patients complained of dizziness, but rotary chair testing was normal across participants for whom testing occurred. CONCLUSION:Patients with GATA3 mutation present with early-onset sensorineural hearing loss (SNHL). DPOAEs were absent, supporting outer hair cell dysfunction, whereas ABRs were present and robust. Rotational vestibular testing revealed no evidence of abnormal horizontal semicircular canal function.

SUBMITTER: Chien WW

PROVIDER: S-EPMC4108448 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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Auditory and vestibular phenotypes associated with GATA3 mutation.

Chien Wade Wei-De WW Leiding Jennifer W JW Hsu Amy P AP Zalewski Christopher C King Kelly K Holland Steven M SM Brewer Carmen C

Otology & neurotology : official publication of the American Otological Society, American Neurotology Society [and] European Academy of Otology and Neurotology 20140401 4

<h4>Objective</h4>To report the auditory and vestibular phenotypes of patients with GATA3 mutation.<h4>Study design</h4>Case series of 6 patients.<h4>Setting</h4>Tertiary referral center.<h4>Patients</h4>All patients had the classic triad of GATA3 deficiency: hypoparathyroidism, hearing loss, and renal dysplasia. Patients (29-60 yr old; mean age, 42.5 yr; 3 male and 3 female subjects) were confirmed to have heterozygous mutations involving GATA3 by Sanger sequencing.<h4>Interventions</h4>Behavio ...[more]

PMID: 24622013

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Project description:BackgroundGATA3 is a transcription factor that is important during development and plays a role in differentiation and activity of immune cells, particularly T cells. Abnormal T cell function is found in autoimmune arthritis. We present the first known case of autoimmune arthritis associated with a novel GATA3 mutation.MethodsWhole exome sequencing of the proband was performed on a clinical basis. Peripheral blood mononuclear cells (PBMCs) were collected from the proband, healthy sibling, and parent. cDNA prepared from RNA was analyzed with polymerase chain reaction and Sanger sequencing. Intracellular proteins were assessed by immunoblot of PBMC homogenates. GATA3 in vitro activity was measured in HeLa cell cultures expressing a mammalian expression vector containing GATA3 or mutants generated by site-directed mutagenesis. GATA3 transcriptional activity was examined using a luciferase reporter assay system. T helper cell ex vivo function was evaluated by stimulating PBMCs to differentiate into effector T cells along Th0, Th1, Th2, and Th17 lineages, and re-stimulating effector cells to secrete cytokines. Cytokine production was measured by enzyme-linked immunosorbent assay.ResultsThe proband is the first known case of autoimmune arthritis associated with a mutation in GATA3. The proband M401VfsX106 protein is expressed and has a dominant negative function on GATA3 transcriptional activity. The proband PBMCs have markedly increased differentiation along the Th1 and Th17 pathways, with decreased differentiation along the Th2 pathway. Unexpectedly, Th0 cells from the proband express high levels of IFNγ.ConclusionsOur research presents the first known case of autoimmune arthritis associated with a mutation in GATA3. This work expands the phenotypic spectrum of GATA3 mutations. It reveals the novel insight that decreased and altered GATA3 activity coincides with autoimmune arthritis. This work suggests that modulation of GATA3 may be a therapeutic approach for patients with autoimmune arthritis.

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Auditory and vestibular phenotypes associated with GATA3 mutation.

Publications

Auditory and vestibular phenotypes associated with GATA3 mutation.

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