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Identification of Three Novel Mutations in the GATA3 Gene Responsible for Familial Hypoparathyroidism and Deafness in the Chinese Population

Departments of Laboratory Medicine (W.-Y.C., H.-W.Cha, K.-S.T.) and Internal Medicine (W.-Y.C., L.-T.Y, K.-S.T.), National Taiwan University Hospital, Taipei 100, Taiwan; and Department of Internal Medicine (H.-W.Che), Lo-Tung Pohai Hospital, Ilan 256, Taiwan

Address all correspondence and requests for reprints to: Keh-Sung Tsai, M.D., Ph.D., Department of Laboratory Medicine, National Taiwan University Hospital, No. 7, Chung-Shan South Road, Taipei 100, Taiwan. E-mail: kstsaimd{at}ha.mc.ntu.edu.tw.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Background: Familial hypoparathyroidism may be caused by mutations of several genes. The CaSR and GATA3 genes are the two candidates most commonly responsible for this condition.

Objectives: We collected five unrelated families with familial hypoparathyroidism and examined their CaSR and GATA3 genes.

Methods: Blood samples from these five families and 50 ethnically matched unrelated controls were acquired. Biochemistry screening and formal audiogram were performed to evaluate the affected individuals. All the exons and exon-intron boundaries of the GATA3 and CaSR genes were sequenced.

Results: We identified three novel mutations in the GATA3 gene responsible for familial hypoparathyroidism and deafness: 1) a frameshift deletion occurring in codon 160 (478delG) was hypothesized to disrupt dual zinc fingers as well as one transactivating domain; 2) a donor splice site mutation at exon 4/intron 4 boundary (IVS4 + 2 T to GCTTACTTCCC) was predicted to lead to truncated GATA3 proteins that lack both N- and C-terminal zinc-containing fingers; and 3) a missense mutation R353S was predicted to disrupt the helical turn and thus changed the angle between the C-terminal zinc finger and the adjacent C-terminal tail. Except for a previously described polymorphism, G990R, we did not find any genetic variants in the CaSR gene.

Conclusions: This is the first article presenting mutations of the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. Our results expand the spectrum of mutations and report the first splice donor site mutation of the GATA3 gene. In contrast, we do not find causal sequence variants of the CaSR gene from our collection of familial hypoparathyroidism.

	Introduction

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FAMILIAL HYPOPARATHYROIDISM is an unusual condition that may be observed as an isolated defect caused by mutation in the calcium-sensing receptor gene (CaSR; MIM 601199), PTH gene (MIM 168450), or GCM2 gene (MIM 603716) (1, 2, 3, 4, 5, 6, 7, 8) or as a component of a more widespread disorder, such as autoimmune polyglandular syndrome type I (MIM 240300) (9); DiGeorge’s syndrome (MIM 188400) (10); or hypoparathyroidism, sensorineural deafness, and renal anomalies (HDR) syndrome (MIM 146255) (11, 12, 13, 14, 15, 16). It can be inherited in an autosomal dominant (2, 3, 4, 6, 8, 11, 12, 13, 14, 15, 16), autosomal recessive (1, 5, 7), or X-linked recessive (17, 18) pattern. After excluding cases of pseudohypoparathyroidism and any immunological disorder, autosomal dominant inheritance seems to be the most common pattern of familial hypoparathyroidism. In view of reports about autosomal dominant hypoparathyroidism, mutations of the calcium-sensing receptor (CaSR) and GATA3 genes were most common.

In 1994, Finegold et al. (19) demonstrated a linkage of autosomal dominant hypocalcemia to chromosome 3q13, which harbors the gene for the CaSR. The CaSR is expressed in tissues involved in calcium homeostasis, including parathyroid gland, thyroid C-cell, kidney, and bone. In parathyroid cells, binding of calcium ion to CaSR decreases PTH secretion by acting as a calcium sensor. In kidney, CaSR activation inhibits the reabsorption of calcium (20). It has been estimated that approximately 40% of cases of idiopathic hypoparathyroidism were harboring activating CaSR mutations (21). Recently GATA3, a member of the GATA-binding family of transcription factors, was shown to be involved in human HDR syndrome (11, 12, 13, 14, 15, 16), which has an autosomal dominant inheritance pattern. GATA3 is a dual zinc finger transcription factor. Human GATA3 expression has been detected in the developing parathyroid gland, inner ear, and kidney, together with thymus and central nervous system (22).

As a candidate gene approach, we investigated patients with familial hypoparathyroidism for the GATA3 and CaSR abnormalities.

	Patients and Methods

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Patients and controls

The diagnosis of familial hypoparathyroidism was based on the family history and presence of hypocalcemia and hyperphosphatemia in association with low or an inappropriately normal level of serum intact PTH (i-PTH). Patients with postsurgical hypoparathyroidism were excluded. None of the patients had any features, such as mucocutaneous candidiasis or facial abnormalities, that could be suggestive of hypoparathyroidism related to the polyglandular autoimmune syndrome type I or DiGeorge’s syndrome. Blood samples from the patients, their family members, and 50 ethnically matched unrelated controls were acquired after having obtained informed and written consent from each participant according to a protocol reviewed and approved by the local ethical research committee. Genomic DNA was extracted from 0.2 ml of whole blood using a commercial DNA extraction kit (NucleoSpin blood; Macherey-Nagel Gmbh & Co. KG, Düren, Germany) according to the manufacturer’s protocol.

Clinical laboratory investigations

All patients and their family members were evaluated both clinically and biochemically. Plasma creatinine, albumin, total calcium, and phosphorus concentrations were measured using commercially available diagnostic kits according to the manufacturer’s instructions. Specifically, serum i-PTH concentrations (biologically active molecule, 1–84 amino acids full length) were measured using a two-site immunochemiluminometric assay on an Immulite 2000 machine (Diagnostics Product Corp., Los Angeles, CA). Urinalysis, nephrosonography, and formal audiogram were performed to evaluate renal and hearing impairment of all the probands and some of the family members.

Mutation detection and analysis

All the coding exons and exon-intron boundaries of the GATA3 and CaSR genes were amplified by PCR as described (12, 23). Subsequently, the PCR products were purified and subjected to cycle sequencing reaction by a BigDye terminator cycle sequencing kit (version 3.1; Applied Biosystems, Foster City, CA). All the genetic variants detected in the probands, which were confirmed by repeat DNA sequence analysis on independently obtained PCR products, were demonstrated to cosegregate with the disorder and to be absent in the DNA obtained from 50 unrelated individuals. Restriction enzyme genotyping using BsmF I was performed to determine the disease segregation pattern of A1059T (amino acid R353S) gene variant within the family as well as the frequency in 100 normal chromosomes.

To examine gene features, like intron/exon boundaries, the HMM-based gene structure predictor is useful. We used the FGENESH program (www.softberry.com) based on the consensus sequence of exon-intron junctions (ag ... gt rule of intronic sequence) as well as on the codon usage within ORF to predict the effect of the splice donor mutation.

Based on the determined NMR structure of C-terminal DNA binding domain of GATA1 (24), this homologous domain of GATA3 consists of a core that contains a zinc coordinated by four cysteines and a carboxyl-terminal tail. The core interacts with the major groove of the DNA, and the carboxyl-terminal tail wraps around into the minor groove. The residue 353 of human GATA3 is located in the long loop that connects the core and the carboxyl-terminal tail. We used the NNPredict software (http://www.cmpharm.ucsf.edu/~nomi/nnpredict.html) to determine the effect of R353S on human GATA3 structure. Besides, key amino-acid positions that are important for maintaining the three-dimensional structure of a protein and/or its functions are often under strong evolutionary constrains. Thus, the biological importance of a residue often correlates with its level of evolutionary conservation within the protein family. ConSurf (http://consurf.tau.ac.il/) (25, 26) is a web-based tool that automatically calculates evolutionary conservation scores and maps them on protein structures. The run was carried out using default parameters and a PDB file that was acquired from CPHmodels 2.0 server (http://www.cbs.dtu.dk/services/CPHmodels/) (27).

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
Clinical findings

Twelve patients with familial hypoparathyroidism from five unrelated families were ascertained (Table 1). In these 12 cases, age at onset of hypoparathyroidism varied from 7 to 50 yr; six were female. Unexplained hypocalcemia (median 1.58 mM) and hyperphosphatemia (median 1.74 mM) were present in eight patients. This was associated with tetany in six patients and seizure in two patients. Computerized tomography of the head performed in those two patients (C/II.3 and D/II.1) with grand mal seizure showed calcification at bilateral cerebrum, basal ganglia, and frontal white matter. Bilateral sensorineural hearing loss was identified in three probands and their family members (families A, B, and C). In addition, renal lesion was radiologically confirmed in one case (patient B/III.2). When she was 5 yr old, renal insufficiency was noted (creatinine clearance 39 ml/min, normal range 120–140 ml/min). Nephrosonography disclosed small size of the kidneys (Table 1). Intravenous pyelography showed vesicoureteral reflux at both sides. Abdominal magnetic resonance imaging revealed renal hypoplasia with lobulated contour in kidney shape. On the last examination at age 16 yr, bilateral contracted kidneys (right/left side = 5.9/6.5 cm) with chronic renal failure were noticed.

Direct sequencing of the CaSR gene revealed the sequences in coding exons, and splice junctions were well conserved except one gene variant: an A-to-G transition at nucleotide 2968 (starting from ATG) in exon 7. This change resulted in a substitution of arginine for glycine (G990R) and was present in one or both alleles in nine of the 12 cases. The frequencies of A/A, A/G, and G/G genotypes in the patients were 8.3, 66.7, and 25%, respectively. It was noted that neither the 990G allele nor 990R allele cosegregated with the hypocalcemia/hypoparathyroidism within the families we studied. This variant, G990R, was previously reported as a benign polymorphism without contribution to hypocalcemia (23, 28).

Sequence analysis of the GATA3 gene disclosed three heterozygous genetic variants. The first, in family A, was a single-base deletion at nucleotide 478 of the cDNA sequence (478delG) located in exon 3 (Fig. 1A). This variant is predicted to result in a frameshift from codon 160 and a premature termination at codon 194. This mutation was present only in the affected family members and was not identified in any of the unaffected relatives or ethnically matched controls. The second sequence variant, found in family B, involved a t to gcttacttccc substitution of the invariant gt in junction of exon-intron 4 (IVS 4 + 2 T GCTTACTTCCC mutation) (Fig. 1B). This mutation occurred in the affected family members and not in the unaffected relatives and control samples. The FGENESH correctly predicted the gene structures, including coding regions through exon 2 to exon 5, of the reference GATA3 gene sequence. In contrast, exon 4 was skipped and the fusion of exons 3 and 5 leads to a reading frameshift at position V260 in this splice donor mutant (Fig. 2). Family C contained a heterozygous A to T transversion at nucleotide 1059 (1059A > T) of the GATA3 cDNA sequence (Fig. 1C). This mutation resided in exon 6 and was predicted to result in the substitution of serine for an arginine residue at position 353 of the GATA3 amino-acid sequence. This mutation was not seen in sequences from unaffected relatives. The base change created a BsmF I restriction site that facilitated screening of control samples. All affected family members demonstrated the presence of the BsmF I restriction site; however, no digestion was observed in unaffected family members or an additional 50 unrelated control samples. Using the ConSurf server (25, 26), we found that R353 is extremely well conserved among various homologous proteins in humans and across species (score = 9; range 1–9; calculation performed on 50 unique sequences) (Fig. 3). The three-dimensional structure of the carboxyl-terminal DNA binding domain of human GATA3 and the position of R353 were shown in Fig. 3. This mutant, R353S, was predicted to disrupt the helix turn composed of residue 355 to 358 by using the NNPredict software with alpha/beta tertiary structure class for prediction.

View larger version (28K): [in this window] [in a new window]   FIG. 1. Results of mutation analysis. The wild-type sequences are given for comparison (upper panels). Arrow denotes mutation site. A, Direct sequencing reveals a heterozygous G deletion at position 478 of the GATA3 cDNA sequence. This mutation was identified in case II.2, III.1, and III.2 of family A. B, Sequence analysis disclosed heterozygous mutant sequence in case II.2, III.2 of family B. This splice donor mutation, IVS4 + 2 T>GCTTACTTCCC, in the GATA3 gene cosegregated with the hypoparathyroidism and hearing loss phenotypes in family B. C, Sequence of antisense strand in exon 6 in family C, Arrow denotes heterozygous A to T transversion at nucleotide 1059 of the cDNA sequence. The variant is predicted to result in the substitution of serine for an arginine residue at position 353 of the GATA3 amino-acid sequence. Cosegregation of this R353S mutation and its heterozygosity in the affected members (II.3, III.1, and III.2) were demonstrated. This mutation was not detected in 100 chromosomes from 50 unrelated normal individuals.

View larger version (13K): [in this window] [in a new window]   FIG. 2. Ideogram of putative splicing consequence of the IVS 4 + 2 T GCTTACTTCCC mutation. Introns and exon 2 of the GATA3 gene are not drawn to scale. The FGENESH correctly predicts gene structure, including coding regions in exons 3–5, of the reference GATA3 sequence (upper panel). By contrast, the novel t to gcttacttccc substitution at the splice donor site of intron 4 results in exon 4 skipping (middle panel) and shifting of the open reading frame (bottom panel).

View larger version (44K): [in this window] [in a new window]   FIG. 3. Surface mapping of phylogenetic information of the C-terminal zinc-containing DNA binding domain (residues 312–375 of cDNA) of human GATA-3. It is presented using a space-filling (A) and cartoon model (B). The amino acids are colored by their conservation grades using the color-coding bar, with turquoise through maroon indicating variable through conserved. Amino-acid positions, for which the inferred conservation level was assigned with low confidence, are marked with light yellow. The residual 353 of the human GATA3 is colored maroon. The three-dimensional structure of the C-terminal DNA binding domain of human GATA3 was based on the NMR structure of that of chicken GATA1 (protein code: 2gatA). Arrow indicates R353. The helical turn (composed of residues 355–358) and carboxyl-terminal tail (composed of residues 363–370) of this DNA binding domain of human GATA3 are shown in the cartoon model.

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

View larger version (21K): [in this window] [in a new window]   FIG. 4. Familial hypoparathyroidism pedigrees. Arrow denotes the proband in each family, asterisks indicate subjects who underwent blood sampling, and filled symbols in each quartered area represent the features in affected family members.

The possibility that the R353S substitution found in family C might be a rare polymorphism cannot be excluded formally, despite the absence of this polymorphism in 100 chromosomes from unaffected controls because functional studies have not been performed. However, the arginine at codon 353 is located within the C-terminal zinc-containing DNA binding domain and is extremely conserved among various homologous proteins in humans and across species, suggesting the biological importance of this residue. Thus, the R353S substitution is considered to be a causative mutation rather than a rare polymorphism. This mutant, R353S, was predicted to disrupt the helix turn composed of residues 355–358. This would lead to a change of directionality of the carboxyl-terminal tail, which is composed of residues 363–370 and is an essential determinant of specific DNA binding in the minor groove (24). The complex of zinc-containing DNA binding domain resembles a hand holding a rope with the palm and fingers representing the protein core, and the thumb, the carboxyl-terminal tail. The long axis of the protein core lies at an angle of approximately 40° to the base planes of the DNA, whereas the carboxyl-terminal tail is approximately parallel to the base planes (24). Thus, change of the angle between the core and carboxyl-terminal tail would be expected to have a significant impact on the specific function of this transcription factor.

In conclusion, the present study, presenting three newly found mutations, is the first article presenting mutations of the GATA3 gene responsible for familial hypoparathyroidism and deafness in the Chinese population. Our results expand the spectrum of disease-causing mutations, provide further evidence that HDR is caused by the haploinsufficiency of GATA3, and report the first splice donor mutation. The commonly described polymorphism, G990R, and mutations in the CaSR gene are not linked to familial hypoparathyroidism in the group of patients we studied. To our knowledge, literatures about mutations in the CaSR gene leading to hypoparathyroidism were absent in our population. Neither the GATA3 nor the CaSR abnormalities were identified in the remaining two families. Additional studies are required to determine the involvement of other regions including intronic and regulatory sequences, or other candidate genes, in the pathogenesis of familial hypoparathyroidism. In our opinion, mutations of the GATA3 gene should be considered in patients with a coexistence of family hypoparathyroidism and sensorineural hearing loss, despite of absence of renal involvement. Besides, it is crucial to evaluate the auditory and renal functions in all patients with familial hypoparathyroidism.

	Acknowledgments

 
We acknowledge the help of the families for participating in the present study. We are grateful to the Department of Medical Research, National Taiwan University Hospital, for DNA sequencing services.

	Footnotes

 
Disclosure summary: The authors have nothing to disclose.

First Published Online August 15, 2006

Abbreviations: CaSR, Calcium-sensing receptor; HDR, hypoparathyroidism, sensorineural deafness, and renal anomalies; i-PTH, intact PTH.

Received April 21, 2006.

Accepted August 3, 2006.

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Top Abstract Introduction Patients and Methods Results Discussion References

 

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Chiu, W.-Y. Articles by Tsai, K.-S. Search for Related Content PubMed PubMed Citation Articles by Chiu, W.-Y. Articles by Tsai, K.-S. Related Collections Calcium and Bone Metabolism