-
Human Molecular Genetics Sep 2013HDR syndrome (also known as Barakat syndrome) is a developmental disorder characterized by hypoparathyroidism, sensorineural deafness and renal disease. Although genetic...
HDR syndrome (also known as Barakat syndrome) is a developmental disorder characterized by hypoparathyroidism, sensorineural deafness and renal disease. Although genetic mapping and subsequent functional studies indicate that GATA3 haplo-insufficiency causes human HDR syndrome, the role of Gata3 in sensorineural deafness and auditory system development is largely unknown. In this study, we show that Gata3 is continuously expressed in the developing mouse inner ear. Conditional knockout of Gata3 in the developing inner ear disrupts the morphogenesis of mouse inner ear, resulting in a disorganized and shortened cochlear duct with significant fewer hair cells and supporting cells. Loss of Gata3 function leads to the failure in the specification of prosensory domain and subsequently, to increased cell death in the cochlear duct. Moreover, though the initial generation of cochleovestibular ganglion (CVG) cells is not affected in Gata3-null mice, spiral ganglion neurons (SGNs) are nearly depleted due to apoptosis. Our results demonstrate the essential role of Gata3 in specifying the prosensory domain in the cochlea and in regulating the survival of SGNs, thus identifying a molecular mechanism underlying human HDR syndrome.
Topics: Animals; Apoptosis; Cochlear Duct; Disease Models, Animal; Ear, Inner; GATA3 Transcription Factor; Gene Expression Regulation, Developmental; Hair Cells, Auditory; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Mice; Mice, Knockout; Nephrosis; Sensory Receptor Cells; Spiral Ganglion
PubMed: 23666531
DOI: 10.1093/hmg/ddt212 -
CEN Case Reports May 2021HDR syndrome is characterized by the triad of primary hypoparathyroidism, sensorineural hearing loss and renal malformation with widely variable manifestations. It is an...
HDR syndrome is characterized by the triad of primary hypoparathyroidism, sensorineural hearing loss and renal malformation with widely variable manifestations. It is an autosomal dominant inherited disease caused by a mutation of the GATA3 (NM_001002295.2), which is located on chromosome 10p14. Congenital heart disease, such as tetralogy of Fallot, a typical complication of DiGeorge syndrome, is a rare complication of HDR syndrome. We herein report a case of HDR syndrome coexisting tetralogy of Fallot with a novel mutation, c.964C > T (p.Gln322*). This case suggested that the screening of renal involvement should be carefully performed in patients with a phenotypic combination of hypoparathyroidism and sensorineural hearing loss, to facilitate the early diagnosis of HDR syndrome. In addition, when the deletion of chromosome 22q11.2 is not detected by a fluorescence in situ hybridization analysis in patients exhibiting the partial phenotype of DiGeorge syndrome, the possibility of HDR syndrome should be considered and the renal function should be repeatedly evaluated.
Topics: Abscess; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Kidney Diseases; Mutation; Nephrosis; Tetralogy of Fallot
PubMed: 33159669
DOI: 10.1007/s13730-020-00551-0 -
BMC Pediatrics Jan 2016Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. We report the first detailed case of hypoparathyroidism...
BACKGROUND
Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome is an autosomal dominant disorder. We report the first detailed case of hypoparathyroidism complicated by biliary atresia.
CASE PRESENTATION
A 1-year-old Japanese girl was admitted to our hospital for living donor liver transplantation. She suffered from obstructive jaundice owing to biliary atresia. She also had persistent hypocalcemia. Despite oral calcium and abundant vitamin D supplementation, a laboratory test showed hypocalcemia (1.4 mmol/l) and hyperphosphatemia (2.6 mmol/l). The intact parathyroid hormone level was normal (66 ng/l) with severe vitamin D deficiency (25-hydroxy vitamin D: undetectable levels). There were no rachitic changes in metaphysis on X-rays. Her family history showed that her mother had sensorineural deafness, a low serum calcium level (2.1 mmol/l), hypoplastic left kidney, and a past history of an operation for right vesicoureteral reflux. We suspected that this patient and her mother have hypoparathyroidism, sensorineural deafness, and renal dysplasia syndrome. A heterozygous GATA3 gene mutation (c.736delGinsAT) was found in this patient and her mother, but not in her father.
CONCLUSION
This familial case confirms the importance of family history in the diagnosis of HDR syndrome. Regardless of marked vitamin D deficiency, the complication of hypoparathyroidism prevented the onset of vitamin D deficiency rickets in our patient.
Topics: Abnormalities, Multiple; Biliary Atresia; Female; Frameshift Mutation; GATA3 Transcription Factor; Genetic Markers; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Infant; Nephrosis
PubMed: 26800885
DOI: 10.1186/s12887-016-0550-9 -
Endocrine Journal 2011GATA3 mutations cause HDR (hypoparathyroidism, sensorineural deafness, and renal dysplasia) syndrome and, consistent with the presence of the second DiGeorge syndrome...
GATA3 mutations cause HDR (hypoparathyroidism, sensorineural deafness, and renal dysplasia) syndrome and, consistent with the presence of the second DiGeorge syndrome locus (DGS2) proximal to GATA3, distal 10p deletions often leads to HDR and DiGeorge syndromes. Here, we report on six Japanese patients with GATA3 abnormalities. Cases 1-5 had a normal karyotype, and case 6 had a 46,XX,del(10)(p15) karyotype. Cases 1-6 had two or three of the HDR triad features. Case 6 had no DiGeorge syndrome phenotype except for hypoparathyroidism common to HDR and DiGeorge syndromes. Mutation analysis showed heterozygous GATA3 mutations in cases 1-5, i.e., c.404-405insC (p.P135fsX303) in case 1, c.700T>C & c.708-709insC (p.F234L & p.S237fsX303) on the same allele in case 2, c.737-738insG (p.G246fsX303) in case 3, c.824G>T (p.W275L) in case 4, and IVS5+1G>C (splice error) in case 5. Deletion analysis of chromosome 10p revealed loss of GATA3 and preservation of D10S547 in case 6. The results are consistent with the previous finding that GATA3 mutations are usually identified in patients with two or three of the HDR triad features, and provide supportive data for the mapping of DGS2 in the region proximal to D10S547.
Topics: Adolescent; Adult; Child, Preschool; Chromosomes, Human, Pair 10; DiGeorge Syndrome; Female; Frameshift Mutation; GATA3 Transcription Factor; Gene Deletion; Hearing Loss, Sensorineural; Heterozygote; Humans; Hypoparathyroidism; Male; Mutation; Mutation, Missense; Nephrosis
PubMed: 21242646
DOI: 10.1507/endocrj.k10e-234 -
The Journal of Clinical Endocrinology... Mar 2016Atypical presentations of complex multisystem disorders may elude diagnosis based on clinical findings only. Appropriate diagnostic tests may not be available or...
CONTEXT
Atypical presentations of complex multisystem disorders may elude diagnosis based on clinical findings only. Appropriate diagnostic tests may not be available or available tests may not provide appropriate coverage of relevant genomic regions for patients with complex phenotypes. Clinical whole-exome/-genome sequencing is often considered for complex patients lacking a definitive diagnosis.
CASE DESCRIPTION
A boy who is now 7 years old presented as a newborn with congenital ichthyosis. At 6 weeks of age, he presented with failure to thrive and hypoparathyroidism. At 4 years of age, he was diagnosed with sensorineural hearing loss. Whole-genome sequencing identified novel mutations in GATA3, which causes HDR syndrome (hypoparathyroidism and deafness), and STS, which causes X -linked congenital ichthyosis.
CONCLUSION
Whole-genome sequencing led to a definitive clinical diagnosis in a case where no other clinical test was available for GATA3, and no sequencing panel would have included both genes because they have disparate phenotypes. This case demonstrates the power of whole-genome (or exome) sequencing for patients with complex clinical presentations involving endocrine abnormalities.
Topics: Child; Exome; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Ichthyosis; Male; Mutation; Nephrosis; Sequence Analysis, DNA; Steryl-Sulfatase
PubMed: 26731259
DOI: 10.1210/jc.2015-3704 -
Internal Medicine (Tokyo, Japan) 2013
Topics: Adult; Basal Ganglia Diseases; Calcinosis; Female; Follow-Up Studies; GATA3 Transcription Factor; Genetic Predisposition to Disease; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Mutation; Nephrosis; Neurodegenerative Diseases; Pedigree; Severity of Illness Index; Tomography, X-Ray Computed
PubMed: 23291697
DOI: 10.2169/internalmedicine.52.8911 -
Disease Models & Mechanisms Sep 2013The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation...
The severity of most human birth defects is highly variable. Our ability to diagnose, treat and prevent defects relies on our understanding of this variability. Mutation of the transcription factor GATA3 in humans causes the highly variable hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. Although named for a triad of defects, individuals with HDR can also exhibit craniofacial defects. Through a forward genetic screen for craniofacial mutants, we isolated a zebrafish mutant in which the first cysteine of the second zinc finger of Gata3 is mutated. Because mutation of the homologous cysteine causes HDR in humans, these zebrafish mutants could be a quick and effective animal model for understanding the role of gata3 in the HDR disease spectrum. We demonstrate that, unexpectedly, the chaperone proteins Ahsa1 and Hsp90 promote severe craniofacial phenotypes in our zebrafish model of HDR syndrome. The strengths of the zebrafish system, including rapid development, genetic tractability and live imaging, make this an important model for variability.
Topics: Animals; Craniofacial Abnormalities; Disease Models, Animal; GATA3 Transcription Factor; HSP90 Heat-Shock Proteins; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Injections; Molecular Chaperones; Morpholinos; Mutation; Nephrosis; Phenotype; Zebrafish; Zebrafish Proteins
PubMed: 23720234
DOI: 10.1242/dmm.011965 -
The Journal of International Medical... Oct 2015We describe the case of a 21-year-old male with hypocalcaemia, hyperphosphataemia, recurrent limb twitch, deafness, proteinuria, increased serum creatinine and urea...
We describe the case of a 21-year-old male with hypocalcaemia, hyperphosphataemia, recurrent limb twitch, deafness, proteinuria, increased serum creatinine and urea nitrogen levels, and shrinkage of both kidneys. Brain computed tomography showed intracranial calcifications. The patient was diagnosed with hypoparathyroidism, sensorineural deafness and renal dysplasia (HDR) syndrome. DNA sequence analysis of the GATA3 gene showed a novel de novo mutation, c. 529dupC (p. Arg177profs*126), in exon 2, resulting in a frameshift mutation with a premature stop codon after a new 126 amino acid sequence. We provide further evidence that HDR syndrome is caused by haploinsufficiency of GATA3.
Topics: Base Sequence; Brain; DNA Mutational Analysis; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Infant, Newborn; Male; Molecular Sequence Data; Mutation; Nephrosis; Radiography, Abdominal; Tomography, X-Ray Computed; Young Adult
PubMed: 26268891
DOI: 10.1177/0300060515591065 -
Endocrine Journal 2011GATA3 is a member of the GATA family of transcription factors. Heterozygous GATA3 abnormalities are associated with hypoparathyroidism, sensorineural deafness, and renal...
GATA3 is a member of the GATA family of transcription factors. Heterozygous GATA3 abnormalities are associated with hypoparathyroidism, sensorineural deafness, and renal abnormality (HDR syndrome). However, this triad of symptoms does not occur in all HDR patients and other clinical features may be present in some cases. We report the clinical phenotypes and the molecular analysis of GATA3 in five Japanese HDR patients, including two familial cases. All five patients had hypoparathyroidism and sensorineural deafness, however renal abnormalities were absent in four patients. In addition, two patients with different mutations of GATA3 had female genital tract abnormalities. Sequence analysis of GATA3 demonstrated three novel (R262G, c1063delC and C318) and two reported mutations (c.432insG and c.1051-1G>T). Transient transfection assay using the GATA3 activating reporter system revealed that the transactivating activity of the R262G, c.1063delC, C318S and c.432insG mutants were markedly decreased, indicating that all four mutations are loss-of-function. In conclusion, this study reiterates the clinical variability in HDR syndrome and identifies three novel mutations of GATA3.
Topics: Adolescent; Adult; Child; DNA; Female; GATA3 Transcription Factor; Genitalia, Female; Hearing Loss, Sensorineural; Heterozygote; Humans; Hypoparathyroidism; Infant; Japan; Kidney; Male; Nephrosis; Pedigree; Phenotype; Polymerase Chain Reaction; Sequence Analysis, DNA
PubMed: 21157112
DOI: 10.1507/endocrj.k10e-246 -
Journal of Clinical Research in... Dec 2015Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease, inherited dominantly and found to be related with GATA3 (GATA binding...
Hypoparathyroidism, deafness, and renal dysplasia (HDR; OMIM 146255) syndrome is a rare disease, inherited dominantly and found to be related with GATA3 (GATA binding protein 3) gene mutations. A 13-year and 8-month-old boy who presented with hypocalcemia was diagnosed with hypoparathyroidism. He also had dysmorphic facial features, renal anomaly (pelvic kidney), and mild sensorineural hearing loss. His cranial computed tomography revealed multiple calcifications in bilateral centrum semiovale, corona radiata, and basal ganglions suggesting a persistent hypoparathyroidism. Thus, the presence of triad of HDR syndrome was considered, and genetic analysis using a next-generation sequencer identified a novel de novo missense mutation in exon 4 p.R276Q (c.827G>A) of GATA3 gene. This is the second patient who was reported to have a mutation in GATA3 gene from Turkey. In conclusion, although HDR syndrome is a rare condition, it should be kept in mind in patients with hypoparathyroidism. Classical triad can easily be identified if patients diagnosed with hypoparathyroidism are also evaluated with a urinary tract ultrasound and an audiometer.
Topics: Adolescent; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Male; Mutation, Missense; Nephrosis; Turkey
PubMed: 26777049
DOI: 10.4274/jcrpe.2249