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Endocrinology, Diabetes & Metabolism... Oct 2023Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A...
SUMMARY
Barakat syndrome, also called HDR syndrome, is a rare genetic disorder encompassing hypoparathyroidism (H), sensorineural deafness (D) and renal disease (R). A 64-year-old woman was referred to our endocrinology clinic for a switch in treatment (from dihydrotachysterol to calcitriol). She had progressive sensorineural deafness since the age of 18 and idiopathic hypoparathyroidism diagnosed at age of 36. Her medical history included osteoporosis with hip/spine fractures, nephrolithiasis and a family history of hearing loss, osteoporosis and kidney disease. The patient's clinical presentation indicated Barakat syndrome. Genetic analysis found a GATA3:c.916C>T nonsense variant. Further tests such as audiometry, labs and renal imaging supported the diagnosis. Due to rarity and manifold symptoms, diagnosis can be challenging. Optional GATA3 testing was suggested in 2018, except in cases of isolated sensorineural deafness or renal disease with pertinent family history. In isolated 'H' cases without 'D' and 'R', GATA3 studies are not required, as no haploinsufficiency cases were reported. Given the rise in genetic disorders, physicians should consistently consider rare genetic disorders in patients with suggestive symptoms, even decades after onset. Although diagnosis might not always impact management directly, it aids patients in accepting their condition and has broader family implications.
LEARNING POINTS
There is currently an important increase in genetic and clinical characterization of new orphan diseases and their causative agents. Unbiased re-evaluation for possible genetic disorders is necessary at every consultation. It is essential to recognize the differential diagnosis of idiopathic hypoparathyroidism. The patient's clinical presentation and family history can be important to establish the correct diagnosis. Physicians should not hesitate to search a patient's signs and symptoms online.
PubMed: 38116790
DOI: 10.1530/EDM-23-0018 -
Molecular Genetics and Metabolism... Mar 2024Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene...
BACKGROUND
Hypoparathyroidism, sensorineural deafness, and renal dysplasia (HDR) syndrome (Barakat syndrome) is a rare autosomal dominant disorder caused by mutations in the gene encoding on chromosome 10p14.
METHOD
Informed consent was obtained from a 38-year-old female patient. 5 mL of venous blood was collected and sent for whole-exome sequencing. constructs of both wild-type and mutant were transfected into HEK-293 T cells. Three-dimensional modeling, luciferase-reporter gene test, western blotting and cellular immunofluorescence were used to evaluate the effect of the mutation.
RESULTS
A novel frameshift mutation c. 677dup(p.Pro227AlafsTer77), named P227Afs, was found in . Three-dimensional modeling revealed that the mutation caused the loss of the dual zinc finger structures 1 and 2 (ZNF1 and ZNF2) of the synthesized protein. Expression of wild-type GATA3 produced a six-fold increase in luciferase activity when compared with pcDNA3.1 vector only ( < 0.001), whereas the P227Afs mutant showed no increase. The mutation significantly reduced the transcriptional activity of . Immunofluorescence and western blotting analyses demonstrated that the mutation changed the nuclear location of GATA3 and caused difficulty in nuclearization.
CONCLUSION
A novel heterozygous frameshift mutation in was identified and showed to result in difficult nuclearization, and a dominant-negative effect on the wild-type.
PubMed: 38469092
DOI: 10.1016/j.ymgmr.2024.101063 -
Frontiers in Endocrinology 2023The HDR syndrome is a rare autosomal dominant disorder characterised by Hypoparathyroidism, Deafness, and Renal dysplasia, and is caused by inactivating heterozygous...
The HDR syndrome is a rare autosomal dominant disorder characterised by Hypoparathyroidism, Deafness, and Renal dysplasia, and is caused by inactivating heterozygous germline mutations in the gene. We report an 11-year-old girl with HDR syndrome caused by a heterozygous mutation located at the splice acceptor site of exon 5 of the gene (NM_001002295.2: c.925-1G>T). Functional studies using a minigene assay showed that this splice site mutation abolished the normal splicing of the pre-mRNA and led to the use of a cryptic splice acceptor site, resulting in the loss of the first seven nucleotides (TCTGCAG) of exon 5 in the mRNA. These findings increase the understanding of the mechanisms by which splicing mutations can cause HDR syndrome.
Topics: Female; Humans; Child; RNA Splice Sites; Hypoparathyroidism; Mutation; Deafness; GATA3 Transcription Factor
PubMed: 37600721
DOI: 10.3389/fendo.2023.1207425