GATA3 maintains the quiescent state of cochlear supporting cells by regulating p27kip1

Haplo-insufficiency of the GATA3 gene causes hypoparathyroidism, sensorineural hearing loss, and renal disease (HDR) syndrome. Previous studies have shown that Gata3 is required for the development of the prosensory domain and spiral ganglion neurons (SGNs) of the mouse cochlea during embryogenesis. However, its role in supporting cells (SCs) after cell fate specification is largely unknown. In this study, we used tamoxifen-inducible Sox2CreERT2 mice to delete Gata3 in SCs of the neonatal mouse cochlea and showed that loss of Gata3 resulted in the proliferation of SCs, including the inner pillar cells (IPCs), inner border cells (IBCs), and lateral greater epithelium ridge (GER). In addition, loss of Gata3 resulted in the down-regulation of p27kip1, a cell cycle inhibitor, in the SCs of Gata3-CKO neonatal cochleae. Chromatin immunoprecipitation analysis revealed that GATA3 directly binds to p27kip1 promoter and could maintain the quiescent state of cochlear SCs by regulating p27kip1 expression. Furthermore, RNA-seq analysis revealed that loss of Gata3 function resulted in the change in the expression of genes essential for the development and function of cochlear SCs, including Tectb, Cyp26b1, Slitrk6, Ano1, and Aqp4.

SAT-065 A Novel De Novo GATA3 Gene Mutation in an Adolescent with HDR Syndrome

Background: GATA3 encodes a transcription factor critical for embryonic development of the parathyroid glands, kidney, inner ear, thymus, and the central nervous system. Heterozygous loss-of-function mutations in GATA3 are associated with hypoparathyroidism, sensorineural deafness and renal disease (HDR syndrome). Clinical Case: A 12 yo male with left hip pain underwent a closed reduction for left slipped capital femoral epiphysis. The pre-op evaluation revealed hypocalcemia (serum Ca 7.7 mg/dL; nl: 8.8-10.2), creatinine 0.46 mg/dL (0.5-1.0), TSH 3.16 uU/mL (0.3-4.2), FT4 1.36 ng/dL (0.8-1.8). Oral calcium and vitamin D supplementation was begun, and 2 wks later, follow-up evaluation revealed serum Ca of 9.4 mg/dL, intact PTH 4.6 pg/mL (10-69), phosphorus 5.9 mg/dL (3.3-5.3), 25-OHD 26 ng/mL (30-100), and a normal chromosomal microarray. Bone density (DXA) Z-scores for hip and spine were -1.7 and 0.8, respectively. At age 13 he underwent bilateral osteotomy due to bilateral hip dysplasia and removal of hardware the next year. At age 15 he underwent left total hip replacement for avascular necrosis. In the post-operative period hypocalcemia recurred (5.9-6.7mg/dL), and he was referred for endocrine evaluation. He was of mixed African American and Puerto-Rican descent. He had difficulties in school and required eyeglasses and hearing aids. Past history included congenital scoliosis (right T11-12 rib fusion, wedged L1 vertebra, and incomplete fusion of posterior elements of L4 and L5), a small right kidney (per ultrasound examination), bilateral orchiopexy for undescended testicles (age 2), diagnoses of ADHD (at age 5); sensorineural hearing loss and psoriasis (age 12), and gastroesophageal reflux (age13). Multiple paternal family members were reported to have abnormal calcium levels and hearing/vision problems, but no known diagnosis. On exam, he had no facial dysmorphism, but left supernumerary nipples, lumbar lordosis and thoracic kyphosis, and clinodactyly. He had achieved Tanner 5 secondary sexual characteristics. There was no Chvostek’s sign. Laboratory investigation revealed Ca 7.9 mg/dL, phosphorus 5.9 mg/dL (3.1-4.7), alkaline phosphatase 123 U/L (50-380), 25-OHD 32 ng/mL, intact PTH 10.2 pg/mL. Treatment with calcium carbonate and calcitriol was begun. Whole exome sequencing identified a heterozygous mutation in GATA3 (c.1061C>T, p.Pro354Leu), predicted to be damaging. This variant has not been reported in literature or public database to our knowledge. Conclusion: This case highlights the importance of genetic testing in the setting of unexplained hypoparathyroidism, and identifies a likely novel mutation in GATA3, providing a basis to counsel the family and encourage medical follow up of suspected family members. References: Barakat, A., et al., Familial nephrosis, nerve deafness, and hypoparathyroidism. J Pediatr 91:61-64, 1977

A neonatal case of HDR syndrome and a vascular ring with a novel GATA3 mutation

HDR syndrome (OMIM #146255) is caused by haploinsufficiency of the GATA3 gene. A vascular ring has not been reported in patients with GATA3-associated HDR syndrome. We report a neonatal case of HDR syndrome and a vascular ring that were possibly due to a novel frameshift mutation in the GATA3 gene.

Hypoparathyroidism, Sensorineural deafness and renal disease (Barakat syndrome) caused by a reduced gene dosage in GATA3: a case report and review of literature

Background Barakat syndrome is an autosomal dominant rare genetic disease caused by haploinsufficiency of the GATA binding protein 3 (GATA3) gene. It is also known as HDR syndrome, and is characterized by varying degrees of hypoparathyroidism, sensorineural deafness and renal disease. This is the first report of a heterozygous GATA3 whole gene deletion causing HDR syndrome in a Sri Lankan family. Case presentation A 13-year-old boy with an acute febrile illness, hypocalcaemia and bilateral carpopedal spasm was referred for evaluation. A past medical history of treatment for persistent hypocalcaemic symptoms since the age of 7 months was obtained. Biochemical investigations showed persistent low serum corrected calcium levels with hyperphosphataemia, hypomagnesaemia, low parathyroid hormone levels, hypercalciuria, and low total 25-hydroxy vitamin D levels. His renal functions and renal sonography were normal. Audiometry showed bilateral moderate to severe sensorineural hearing loss. On screening, his mother was also found to have asymptomatic hypocalcaemia, hypomagnesaemia, hyperphosphataemia, hypercalciuria and low total 25-hydroxy vitamin D levels. She had impaired renal functions and chronic parenchymal changes in the renal scan. Audiometry showed bilateral profound sensorineural hearing loss. Genetic analysis using multiplex-ligation dependent probe amplification showed a reduced gene dosage for GATA3 that is consistent with a heterozygous whole gene deletion in both the child and mother. Conclusions This report demonstrates the wide intra-familial phenotypic variability observed in HDR syndrome and adds further to the existing scientific literature on the genotype-phenotype correlation of this syndrome. It highlights the need for HDR syndrome to be considered in the differential diagnosis of persistent hypocalcaemia with sensorineural deafness and/or renal involvement, and for appropriate genetic evaluation to be done to confirm the diagnosis.

A Novel Role for GATA3 in Mesangial Cells in Glomerular Development and Injury

BackgroundGATA3 is a dual-zinc finger transcription factor that regulates gene expression in many developing tissues. In the kidney, GATA3 is essential for ureteric bud branching, and mice without it fail to develop kidneys. In humans, autosomal dominant GATA3 mutations can cause renal aplasia as part of the hypoparathyroidism, renal dysplasia, deafness (HDR) syndrome that includes mesangioproliferative GN. This suggests that GATA3 may have a previously unrecognized role in glomerular development or injury.MethodsTo determine GATA3’s role in glomerular development or injury, we assessed GATA3 expression in developing and mature kidneys from Gata3 heterozygous (+/−) knockout mice, as well as injured human and rodent kidneys.ResultsWe show that GATA3 is expressed by FOXD1 lineage stromal progenitor cells, and a subset of these cells mature into mesangial cells (MCs) that continue to express GATA3 in adult kidneys. In mice, we uncover that GATA3 is essential for normal glomerular development, and mice with haploinsufficiency of Gata3 have too few MC precursors and glomerular abnormalities. Expression of GATA3 is maintained in MCs of adult kidneys and is markedly increased in rodent models of mesangioproliferative GN and in IgA nephropathy, suggesting that GATA3 plays a critical role in the maintenance of glomerular homeostasis.ConclusionsThese results provide new insights on the role GATA3 plays in MC development and response to injury. It also shows that GATA3 may be a novel and robust nuclear marker for identifying MCs in tissue sections.

HDR Syndrome Accompanying Type 1 Diabetes Mellitus and Hypopituitarism

HDR (Hypoparathyroidism, Deafness, and Renal Dysplasia) syndrome is an autosomal dominant disorder characterized by the triad of hypoparathyroidism, sensorineural deafness, and renal disease. Approximately 65% of patients with HDR syndrome have all three of these features, while others have different combinations of these features. We aimed to present a case with primary hypoparathyroidism, hearing loss, and nondiabetic chronic kidney disease and diagnosed as HDR syndrome while being followed up for type 1 diabetes mellitus and hypopituitarism.