A rare case of deafness and renal abnormalities in HDR syndrome caused by a de novo mutation in the GATA3 gene

Martins, Fábio Tadeu Arrojo; Ramos, Berenice Dias; Sartorato, Edi Lúcia

doi:10.1590/1678-4685-gmb-2017-0194

Cited by 3 publications

(2 citation statements)

References 15 publications

(27 reference statements)

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“…; Martins et al . ). Heterozygous null gata3 mice ( gata +/− ) have a complex cochlear pathology, including OHC degeneration as early as 1 month of age, followed by loss of pillar cells, IHCs and nerve fibres (van der Wees et al .…”

Section: Introductionmentioning

confidence: 97%

Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea

Bardhan

Jeng

Waldmann

et al. 2019

The Journal of Physiology

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Key points The physiological maturation of auditory hair cells and their innervation requires precise temporal and spatial control of cell differentiation. The transcription factor gata3 is essential for the earliest stages of auditory system development and for survival and synaptogenesis in auditory sensory afferent neurons. We show that during postnatal development in the mouse inner ear gata3 is required for the biophysical maturation, growth and innervation of inner hair cells; in contrast, it is required only for the survival of outer hair cells. Loss of gata3 in inner hair cells causes progressive hearing loss and accounts for at least some of the deafness associated with the human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome. The results show that gata3 is critical for later stages of mammalian auditory system development where it plays distinct, complementary roles in the coordinated maturation of sensory hair cells and their innervation. Abstract The zinc finger transcription factor gata3 regulates inner ear development from the formation of the embryonic otic placode. Throughout development, gata3 is expressed dynamically in all the major cochlear cell types. Its role in afferent formation is well established but its possible involvement in hair cell maturation remains unknown. Here, we find that in heterozygous gata3 null mice (gata3+/−) outer hair cells (OHCs) differentiate normally but their numbers are significantly lower. In contrast, inner hair cells (IHCs) survive normally but they fail to acquire adult basolateral membrane currents, retain pre‐hearing current and efferent innervation profiles and have fewer ribbon synapses. Targeted deletion of gata3 driven by otoferlin‐cre recombinase (gata3fl/flotof‐cre+/−) in IHCs does not affect OHCs or the number of IHC afferent synapses but it leads to a failure in IHC maturation comparable to that observed in gata3+/− mice. Auditory brainstem responses in gata3fl/flotof‐cre+/− mice reveal progressive hearing loss that becomes profound by 6–7 months, whilst distortion product otoacoustic emissions are no different to control animals up to this age. Our results, alongside existing data, indicate that gata3 has specific, complementary functions in different cell types during inner ear development and that its continued expression in the sensory epithelium orchestrates critical aspects of physiological development and neural connectivity. Furthermore, our work indicates that hearing loss in human hypoparathyroidism, deafness and renal anomaly (HDR) syndrome arises from functional deficits in IHCs as well as loss of function from OHCs and both afferent and efferent neurons.

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Section: Introductionmentioning

confidence: 97%

Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea

Bardhan

Jeng

Waldmann

et al. 2019

The Journal of Physiology

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show abstract

“…Further studies have provided evidence that GATA3 is also crucial for the coordinated maturation of sensory hair cells and their innervation ( Bardhan et al, 2019 ). In humans, the expression of GATA3 is localized to the cochlear duct and the spiral ganglion between weeks 8 and 12 of gestation ( Roccio et al, 2018 ); the loss of GATA3 in inner hair cells leads to hearing loss and accounts for some of the deafness connected to hypoparathyroidism and renal anomaly (HDR) syndrome ( Van Esch et al, 2000 ; Martins et al, 2018 ). Researchers have also demonstrated that GATA3 plays critical roles in neural crest cell development and neuronal differentiation in some cranial neural crest derivatives ( George et al, 1994 ; Lieuw et al, 1997 ; Lakshmanan et al, 1999 ).…”

Section: Discussionmentioning

confidence: 99%

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

Wen

Song

Bai

et al. 2021

Front. Cell Dev. Biol.

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Waardenburg syndrome (WS) is an autosomal dominant inherited disorder that is characterized by sensorineural hearing loss and abnormal pigmentation. SOX10 is one of its main pathogenicity genes. The generation of patient-specific induced pluripotent stem cells (iPSCs) is an efficient means to investigate the mechanisms of inherited human disease. In our work, we set up an iPSC line derived from a WS patient with SOX10 mutation and differentiated into neural crest cells (NCCs), a key cell type involved in inner ear development. Compared with control-derived iPSCs, the SOX10 mutant iPSCs showed significantly decreased efficiency of development and differentiation potential at the stage of NCCs. After that, we carried out high-throughput RNA-seq and evaluated the transcriptional misregulation at every stage. Transcriptome analysis of differentiated NCCs showed widespread gene expression alterations, and the differentially expressed genes (DEGs) were enriched in gene ontology terms of neuron migration, skeletal system development, and multicellular organism development, indicating that SOX10 has a pivotal part in the differentiation of NCCs. It’s worth noting that, a significant enrichment among the nominal DEGs for genes implicated in inner ear development was found, as well as several genes connected to the inner ear morphogenesis. Based on the protein-protein interaction network, we chose four candidate genes that could be regulated by SOX10 in inner ear development, namely, BMP2, LGR5, GBX2, and GATA3. In conclusion, SOX10 deficiency in this WS subject had a significant impact on the gene expression patterns throughout NCC development in the iPSC model. The DEGs most significantly enriched in inner ear development and morphogenesis may assist in identifying the underlying basis for the inner ear malformation in subjects with WS.

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HDR syndrome: Large cohort and systematic review

Rive Le Gouard,

Lafond‐Rive,

Jonard

et al. 2024

Clinical Genetics

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HDR syndrome is a rare disease characterized by hypoparathyroidism, deafness, and renal dysplasia. An autosomal dominant disease caused by heterozygous pathogenic GATA3 variants, the penetrance of each associated condition is variable. Literature reviews have provided some answers, but many questions remain, in particular what the relationship is between genotype and phenotype. The current study examines 28 patients with HDR syndrome combined with an exhaustive review of the literature. Some conditions such as hearing loss are almost always present, while others described as rare initially, do not seem to be so rare after all (genital malformations and basal ganglia calcifications). By modeling pathogenic GATA3 variants found in HDR syndrome, we found that missense variations appear to always be located in the same area (close to the two Zinc Finger domain). We describe new pathogenic GATA3 variants, of which some seem to always be associated with certain conditions. Many audiograms were studied to establish a typical audiometric profile associated with a phenotype in HDR. As mentioned in the literature, hearing function should always be assessed as early as possible and follow up of patients with HDR syndrome should include monitoring of parathyroid function and vesicoureteral reflux in order to prevent complications.

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A rare case of deafness and renal abnormalities in HDR syndrome caused by a de novo mutation in the GATA3 gene

Cited by 3 publications

References 15 publications

Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea

Gata3 is required for the functional maturation of inner hair cells and their innervation in the mouse cochlea

A Model of Waardenburg Syndrome Using Patient-Derived iPSCs With a SOX10 Mutation Displays Compromised Maturation and Function of the Neural Crest That Involves Inner Ear Development

HDR syndrome: Large cohort and systematic review

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