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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 -
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 -
JCEM Case Reports Jan 2023HDR syndrome is a rare genetic disorder caused by mutations in the gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we...
HDR syndrome is a rare genetic disorder caused by mutations in the gene and characterized by hypoparathyroidism, sensorineural deafness, and renal disease. Here, we report case of a 9-month-old male with history of hydronephrosis and sensorineural deafness who presented with febrile seizures. He was found to have hypocalcemia and inappropriately normal parathyroid hormone. His neurologic and infectious workup were negative. Genetic testing revealed a nonsense mutation in the gene, consistent with HDR syndrome. Hypocalcemia was responsive to calcium carbonate and calcitriol treatment. This case highlights hypocalcemia caused by hypoparathyroidism as a potential etiology of seizures. When hypoparathyroidism is detected with either hearing loss or renal disease, HDR syndrome should be considered, and other features of the syndrome should be investigated.
PubMed: 37908274
DOI: 10.1210/jcemcr/luac025 -
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 -
Nutrients May 2023The food frequency questionnaire (FFQ) is designed to capture an individual's habitual dietary intake and is the most applied method in nutritional epidemiology. Our aim...
The food frequency questionnaire (FFQ) is designed to capture an individual's habitual dietary intake and is the most applied method in nutritional epidemiology. Our aim was to assess the relative validity and reproducibility of the FFQ used in the Diet, Cancer, and Health-Next Generations cohort (DCH-NG). We included 415 Danish women and men aged 18-67 years. Spearman's correlations coefficients, Bland-Altman limits of agreement and cross-classification between dietary intakes estimated from the FFQ administered at baseline (FFQ), and the mean of three 24-h dietary recalls (24-HDRs) and the FFQ administered after 12 months (FFQ) were determined. Nutrient intakes were energy-adjusted by Nutrient Density and Residual methods. Correlation coefficients ranged from 0.18-0.58 for energy and energy-adjusted nutrient intakes, and the percentage of participants classified into the same quartile ranged from 28-47% between the FFQ and the 24-HDRs. For the FFQ compared with FFQ, correlation coefficients ranged from 0.52-0.88 for intakes of energy, energy-adjusted nutrients, and food groups, and the proportion of participants classified into the same quartiles ranged from 43-69%. Overall, the FFQ provided a satisfactory ranking of individuals according to energy, nutrient, and food group intakes, making the FFQ suitable for use in epidemiological studies investigating diet in relation to disease outcomes.
Topics: Male; Humans; Female; Reproducibility of Results; Surveys and Questionnaires; Diet; Energy Intake; Diet Records; Diet Surveys; Neoplasms; Denmark; Internet
PubMed: 37242272
DOI: 10.3390/nu15102389 -
Journal of Nutritional Science 2023The present study aims to develop a quantitative food frequency questionnaire (FFQ) to assess free sugar intake as a whole and at the food group levels, retrospectively,...
The present study aims to develop a quantitative food frequency questionnaire (FFQ) to assess free sugar intake as a whole and at the food group levels, retrospectively, over the past 3 months among 4 to 5-year-old preschool children in the Colombo district, Sri Lanka. Then, to assess its reliability and relative validity. In the development phase, three 24-hour dietary recalls (24 hDRs) of 518 preschool children were collected from caregivers. Based on that, a 67-item FFQ was developed, including commonly consumed free sugar-containing food items. The validation study was conducted among another 108 preschool children. The relative validity of the FFQ was assessed by comparing it with the 24 hDRs. The test-retest reliability was assessed by repeated application of the FFQ to the same population after 6 weeks. Wilcoxon sign rank test, cross-classification with weighted Kappa statistic, Spearman rank correlation and Bland-Altman plots were used for comparison. Comparing the free sugar intake calculated by the two methods showed no difference ( = 0⋅13), a good correlation (0⋅89), good agreement in cross-classifying participants (78⋅4 % correctly classified) and a good agreement in Bland-Altman plots. Repeated application of the FFQ yielded; no differences in free sugar intake values ( = 0⋅45) a good correlation (0⋅71), acceptable agreement in cross-classifying participants (52⋅3 % correctly classified) and acceptable agreement in the Bland-Altman plot. Results were the same for all food groups. According to the results, the newly developed quantitative FFQ provides a relatively valid and reliable measure for quantifying free sugar intake among preschool children as a whole or by food group.
Topics: Humans; Child, Preschool; Sri Lanka; Reproducibility of Results; Retrospective Studies; Surveys and Questionnaires; Sugars
PubMed: 36843966
DOI: 10.1017/jns.2023.5 -
Journal of Nutritional Science 2022All dietary assessment methods inevitably introduce measurement errors, which should ideally be considered during data analysis and interpretation. Methodological...
All dietary assessment methods inevitably introduce measurement errors, which should ideally be considered during data analysis and interpretation. Methodological studies should be conducted to address how well a given assessment method captures dietary intake and to highlight the extent and direction of the measurement error. Within a subgroup of the Hordaland Health Study (HUSK3), we examined the relative validity of a web-based food frequency questionnaire (WebFFQ) by comparing its estimates of mean daily intake of nutrients and foods with estimated mean daily intakes from repeated administrations of 24-hour dietary recall interviews (24-HDRs). Men and women born between 1950 and 1951 were recruited from HUSK3. The participants ( 67) completed a WebFFQ and three non-consecutive 24-HDRs over the course of a year. Relative validity was assessed using Spearman's rank correlation, crosstab analysis and Bland-Altman plots. Linear regression models were used to compute the calibration coefficients. The estimated correlation coefficients were acceptable or strong for all nutrients and foods except iodine ( = 0⋅19). The highest correlation coefficient was found for juice ( = 0⋅71), whereas the lowest correlation coefficient was found for iodine ( = 0⋅19). Cross-classification by quartiles categorised more than 72 % of the participants into the same or adjacent quartiles using the two methods. Few data points fell outside the limits of agreement in the Bland-Altman plots. Calibration coefficients ranged from 0⋅10 (wholegrain) to 0⋅81 (alcohol). Our findings suggest that the WebFFQ has reasonable ranking abilities for all the included nutrients and foods, except for iodine.
Topics: Humans; Male; Female; Reproducibility of Results; Surveys and Questionnaires; Eating; Iodine; Internet
PubMed: 36405094
DOI: 10.1017/jns.2022.97 -
Cureus Apr 2022Unlike hyperparathyroidism, hypoparathyroidism is rarely encountered in clinical practice. Usually, it results from surgical resection, an autoimmune phenomenon, or an...
Unlike hyperparathyroidism, hypoparathyroidism is rarely encountered in clinical practice. Usually, it results from surgical resection, an autoimmune phenomenon, or an infiltrative process. Under certain circumstances, one may encounter a genetic etiology of hypoparathyroidism, often combined with myriad other syndromic manifestations. We report a case of a young female with congenital deafness and subacute visual loss. Hypocalcemia and primary hypoparathyroidism were subsequently discovered, and the cause of the vision loss was diagnosed as idiopathic intracranial hypertension, likely secondary to severe primary hypoparathyroidism. The patient was also found to have small bilateral kidneys, with tubular loss of magnesium and calcium, yet with a normal glomerular filtration rate. The constellation of congenital deafness, hypoparathyroidism, and renal dysfunction suggests Barakat syndrome, one of the less common causes of syndromic primary hypoparathyroidism.
PubMed: 35651450
DOI: 10.7759/cureus.24521 -
Scientific Reports Nov 2021Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding...
Transcription factors (TFs) play important roles in many biochemical processes. Many human genetic disorders have been associated with mutations in the genes encoding these transcription factors, and so those mutations became targets for medications and drug design. In parallel, since many transcription factors act either as tumor suppressors or oncogenes, their mutations are mostly associated with cancer. In this perspective, we studied the GATA3 transcription factor when bound to DNA in a crystal structure and assessed the effect of different mutations encountered in patients with different diseases and phenotypes. We generated all missense mutants of GATA3 protein and DNA within the adjacent and the opposite GATA3:DNA complex models. We mutated every amino acid and studied the new binding of the complex after each mutation. Similarly, we did for every DNA base. We applied Poisson-Boltzmann electrostatic calculations feeding into free energy calculations. After analyzing our data, we identified amino acids and DNA bases keys for binding. Furthermore, we validated those findings against experimental genetic data. Our results are the first to propose in silico modeling for GATA:DNA bound complexes that could be used to score effects of missense mutations in other classes of transcription factors involved in common and genetic diseases.
Topics: Binding Sites; Breast Neoplasms; DNA; Female; GATA3 Transcription Factor; Hearing Loss, Sensorineural; Humans; Hypoparathyroidism; Mutation; Nephrosis
PubMed: 34815386
DOI: 10.1038/s41598-021-01832-z -
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