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The Journal of Clinical Endocrinology & Metabolism Vol. 88, No. 6 2916-2921
Copyright © 2003 by The Endocrine Society

Mutations in the PDS Gene in German Families with Pendred’s Syndrome: V138F Is a Founder Mutation

Guntram Borck, Christian Roth, Ursula Martiné, Gabriele Wildhardt and Joachim Pohlenz

Children’s Hospital (G.B., U.M., G.W., J.P.), Johannes-Gutenberg-University of Mainz, D-55101 Mainz; and University Children’s Hospital Bonn (C.R.), D-53113 Bonn, Germany

Address all correspondence and requests for reprints to: Joachim Pohlenz, M.D., Children’s Hospital, Building 109, Johannes Gutenberg-University of Mainz, Langenbeckstrasse 1, D-55101 Mainz, Germany. E-mail: pohlenz{at}mail.uni-mainz.de.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Pendred’s syndrome, an autosomal-recessive condition characterized by congenital sensorineural hearing loss and goiter, is caused by mutations in the PDS gene. Located on chromosome 7q22-q31, it encodes a chloride-iodide transporter expressed in the thyroid, inner ear, and kidney. We investigated the PDS gene of six affected individuals from four unrelated families with Pendred’s syndrome by direct sequencing. PDS mutations were identified in homozygous or compound heterozygous state in all six cases. A homozygous missense mutation leading to the amino acid substitution S133T was detected in a family of Turkish origin. The mutations found in the other affected individuals, who originate from Germany, were V138F/Y530H, V138F/E384G, and V138F/V138F. Because V138F was found in the German patients with Pendred’s syndrome on at least one allele, we genotyped five microsatellite markers located in the PDS region. All affected German individuals shared a common haplotype at three microsatellite markers located close to or within the PDS gene. We therefore concluded that V138F is a founder mutation in our cohort of German families with Pendred’s syndrome.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PENDRED’S SYNDROME (MIM 274600) is an autosomal-recessive disease that is classically characterized by sensorineural hearing loss and enlargement of the thyroid gland (1). Hearing impairment is bilateral, most often congenital, and varies from severe to profound. In the vast majority of cases, malformations of the inner ear are seen on computed tomography (CT) or magnetic resonance imaging (MRI) scans of the temporal bones (2). Such malformations include an enlarged vestibular aqueduct or, less frequently, a Mondini malformation in which the upper turns of the cochlea are hypoplastic and form a common cavity. Goiter usually develops in late childhood to early adulthood but is absent in about one fifth of patients (3). Goiters may be present in euthyroid individuals but subclinical or even overt hypothyroidism is found in about a third of patients with Pendred’s syndrome (3). The diagnosis is confirmed by an abnormal perchlorate discharge test in which in affected individuals perchlorate, given 2 h after the administration of radiolabeled iodide, displaces 15–80% of the accumulated tracer from the thyroid gland, compared with less than 10% in normal controls. More recently molecular analysis of the Pendred’s syndrome gene (PDS) has become possible.

PDS (also known as SLC26A4, MIM 605646) is located on chromosome 7q22.3–7q31.1 and is composed of 21 exons that encode a 780 amino acid protein called pendrin. Pendrin is expressed in the thyroid gland (4, 5), inner ear (4, 6), and kidney (4, 7). It functions as a chloride-iodide transporter in cell expression systems (8). In thyrocytes, pendrin is expressed in the apical membrane (5, 9) in which it presumably transports iodide into the follicular lumen (9). So far, more than 50 PDS mutations have been identified in individuals with Pendred’s syndrome (4, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25), including patients with hearing loss because of enlarged vestibular aqueduct without goiter (26, 27, 28) and individuals with nonsyndromic recessive deafness DFNB4 (29). Several of these mutations are recurrent and for some of them (i.e. 1421delT, L236P, E384G, and T416P) a founder effect has been proposed based on the identification of common disease-associated haplotypes (4, 17, 20).

Because so far no detailed studies have been performed on German patients with Pendred’s syndrome, we investigated four families on the molecular level, three of them originating from Germany and one from Turkey. Our interest was focused on the question of whether recurrent mutations are due to a founder effect or to a mutational hot spot.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Sequence analysis of the PDS gene

After written informed consent was obtained from all available family members, DNA was extracted from peripheral blood leukocytes following standard protocols. For mutation detection, all 21 exons of the PDS gene were amplified by PCR as described previously (4, 17). Exons 1, 3–10, 14, 18, and 21 were amplified using the primers and PCR conditions described by Everett et al. (4). Primers and PCR conditions described by Coyle et al. (17) were used to amplify exons 2, 11–13, 15–17, 19, and 20. An exception was the forward primer for exon 17, which was 5'-CAAGGAACAGTGTGTAGGT-3'. After amplification, PCR products were run on a 2% agarose gel, stained with ethidium bromide, and visualized under UV light.

PCR products were purified and then sequenced directly in both directions using an automated sequencing system (A377, PE Applied Biosystems, Weiterstadt, Germany). The numbering of the nucleotides and nomenclature of the mutations follows published recommendations, with the A of the translation initiation codon ATG denoted as +1 (30). To facilitate comparison with other reported mutations, numbering of nucleotides is also given (in parentheses) according to the sequence published by Everett et al. (4).

Dde I restriction assay

The 412G-T (636G-T, V138F) mutation (see Results) abolishes a recognition site for the restriction endonuclease Dde I. Restriction enzyme digestion with Dde I was performed as recommended by the manufacturer (New England Biolabs, Inc., Schwalbach, Germany). After digestion, PCR products were separated on a 2% agarose gel, stained with ethidium bromide, and visualized under UV light. In a normal individual, the PCR product of exon 4 (272 bp) is cut into two fragments of 178 bp and 94 bp. The mutation 412G-T (636G-T) abolishes a Dde I recognition site, leaving the 272-bp fragment uncut in homozygotes, whereas heterozygotes have three bands: 272, 178, and 94 bp.

Haplotype analysis

For haplotype analysis, five highly polymorphic dinucleotide repeat microsatellite markers from the PDS genomic region were genotyped according to standard protocols: D7S501, D7S2420, D7S496, D7S2459, and D7S2456 (31). The physical maps of these markers are given according to the ongoing sequencing project of the human genome (see the University of California at Santa Cruz home page at www.genome.ucsc.edu; accessed June 2002). D7S2459 is located in intron 10 of the PDS gene, and the other microsatellite markers map proximally (D7S501, D7S2420, and D7S496) and distally (D7S2456) to the gene, D7S501 and D7S2456 being 1.04 Mbp apart. According to the determined product size, alleles were arbitrarily numbered to allow intra- and interfamilial comparison.

Laboratory testing

In families A, B, and D, serum TSH, total T4, total T3, free T4, and free T3 concentrations were measured with chemoluminescent immunoassays (Chiron Corp., Fernwald, Germany), and thyroglobulin was measured by a chemoluminescence enzyme immunoassay (DPC, Biermann, Germany). The methods used for thyroid function testing in family C are not known to the authors.

Subjects

Family A The pedigree of family A is shown in Fig. 1Go. Patient A II-1 was born in 1985 to nonconsanguineous parents of Turkish origin. His mother has a goiter; a maternal aunt and a paternal uncle are reported to be hypothyroid. At 4 wk, patient A II-1 was evaluated at our hospital because of elevated serum TSH levels. The result of the newborn TSH screening is not known. On physical examination his skin was dry, and there was hypotonia but no goiter. Thyroid function tests showed an elevated TSH (281 mU/liter; normal 0–8). Total T3 was 1.9 nmol/liter (normal 1.2–2.8), total T4 15.6 nmol/liter (normal 65–170), and free T4 1.8 pmol/liter (normal 9–25.5). Congenital primary hypothyroidism was diagnosed so that thyroid hormone replacement therapy was initiated and adjusted subsequently for his age and weight. At 13 yr of age, while on T4, his TSH was 1.87 mU/liter and his thyroglobulin was 30.7 ng/ml (normal <55).



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  		Figure 1. Automated fluorescence-based sequencing chromatogram of exon 4 of the PDS gene amplified from genomic DNA. The pedigree of family A is shown. The propositus (II-1) is indicated by an arrow. He is homozygous for the mutation (A) in codon 133, which leads to an amino acid change from a wild-type serine to a mutant threonine (S133T). All other family members are heterozygous (A and T) carriers of the mutation.

 
Apart from a delayed onset of speech, his development was normal and testing at 2 yr of age showed that his intelligence was in the low normal range. At the same time, he was first evaluated for hearing loss. Repeated pure tone audiometries and auditory brain stem response testing showed severe to profound bilateral hearing impairment. Cranial CT scans at 1 and 2 yr of age were normal, but detailed imaging of the inner ears was not done.

Both his clinically unaffected parents and an unaffected sister were euthyroid and had normal thyroid function tests (data not shown).

Family B Two children are affected in this family (Fig. 2Go). Patient B II-1, a 9-yr-old girl, was born after 41 wk gestation to healthy nonconsanguineous parents. Weight at birth was 3570 g, length 53 cm. She presented muscular hypotonia and feeding problems. Newborn TSH screening revealed an elevated TSH of 131 mU/liter (normal < 15 mU/liter). On physical examination at 2 wk, there was dry skin and an open posterior fontanel but no goiter. Thyroid function tests showed elevated serum TSH concentration of 11.2 mU/liter (normal 0.1–4.5) but normal serum T4 of 134 nmol/liter (normal 65–170), T3 of 2.3 nmol/liter (normal 1.2–2.8), free T4 of 15.9 pmol/liter (normal 9–25.5), and free T3 of 7.4 pmol/liter (normal 2.5–8.5). Thyroid hormone replacement therapy was started. Perchlorate discharge test performed at 3 yr of age was positive with a loss of 29% (normal < 10%) of radioiodide accumulated at 2 h in the thyroid gland. There was no goiter and ultrasound performed at 9 yr showed a normally positioned thyroid gland of normal size. She was first evaluated for hearing loss at the age of 5 months. Audiometry showed variable hearing reactions between 85 and 100 dB. Auditory brain stem response potentials were not reproducible at 110 dB, indicating bilateral profound hearing loss. CT and MRI scans of the temporal bones revealed an enlarged vestibular aqueduct bilaterally. She received hearing aids and at age 2 yr a cochlear implant on the right side.



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  		Figure 2. Pedigrees of families B, C, and D showing the haplotypes for all five investigated microsatellite markers of the PDS region. Mutant alleles are indicated by colored symbols. All individuals having two mutant alleles are clinically affected, whereas the unaffected heterozygous individuals have one wild-type allele (white). All different wild-type alleles are uncolored and shaded differently. Haplotypes are aligned with each individual symbol. The mutant allele V138F is colored in red to facilitate identification of the common haplotype in all individuals with this mutation.

 
Patient B II-2, a boy, was evaluated for Pendred’s syndrome at his first day of life because the diagnosis of Pendred’s syndrome was known in his sister. Birth weight at 41 wk was 3470 g and length 52 cm. TSH was 91.7 mU/liter, T4 104 nmol/liter, T3 2.3 nmol/liter, and free T4 11.7 pmol/liter. T4 substitution was started on d 2. On d 4 audiological evaluation disclosed no reproducible otoacoustic emissions; brain stem auditory responses at 7 d showed potentials at 60 dB, indicating moderately severe hearing loss. At 7 months hearing aids were provided. Hearing loss was progressive with thresholds at 55 dB on the right side and 80 dB on the left at 4 yr. CT or MRI examination of the temporal bones in patient 3 was not performed.

The clinically unaffected father was euthyroid (data not shown). Their mother’s thyroid function was not evaluated.

Family C The child (C II-1) was evaluated at 11 yr of age because his father (C I-1) and a paternal aunt (C I-2) were known to have Pendred’s syndrome (Fig. 2Go). He was clinically unaffected and had a serum TSH level of 2.42 mU/liter (normal 0.3–4) and a T4 concentration of 95.6 nmol/liter (normal 58–147) at 10 yr of age. No further clinical details on this family were available.

Family D Pendred’s syndrome was diagnosed in this 14-yr-old boy (D II-1, Figs. 2Go and 3Go) based on congenital primary hypothyroidism (elevated serum TSH level at newborn screening test) and profound bilateral fluctuating hearing loss. He was on thyroid hormone replacement since the age of 14 d, and his replacement dose was adjusted with age. When investigated, thyroid function tests were all within the normal range.



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  		Figure 3. Pedigree of family D and results of genotyping for V138F. In a wild-type individual, the PCR product of exon 4 of the PDS gene (272 bp) produces fragments of 178 bp and 94 bp when digested with Dde I. V138F abolishes the Dde I recognition site. Whereas in the homozygous propositus (II-1) the digested PCR product remains uncut, I-1, I-2, and I-3 are heterozygous for the mutation, showing three bands (272 bp, 178 bp, and 94 bp). I-4 is not a carrier of the mutant allele.

 
Families B, C, and D are from Germany.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Mutation detection in the PDS gene

In all affected individuals, we identified PDS mutations in homozygous or compound heterozygous state. All these mutations have been found to cause Pendred’s syndrome before.

A homozygous missense mutation in exon 4 was detected in patient A II-1: 398T-A, 621T-A according to Everett et al. (4) (Fig. 1Go). This mutation leads to a replacement of a serine residue by a threonine (S133T) in the second predicted transmembrane domain of pendrin. Both clinically unaffected parents are heterozygous for the mutation (Fig. 1Go). S133T was not detected in 50 unaffected unrelated Caucasian control subjects (100 alleles) by direct sequencing of PDS exon 4.

The mutations found in the other three affected individuals, who originate from Germany, were V138F/Y530H, V138F/E384G, and V138F/V138F (data not shown). Patients B II-1 and B II-2 were found to be compound heterozygotes: We detected a G-to-T transversion at nucleotide 412 (636, exon 4) leading to the amino acid substitution V138F and a transition [1588T-C (1812T-C)] in exon 14 resulting in a substitution of tyrosine by histidine (Y530H). The father and mother were heterozygous for Y530H and V138F, respectively. Sequencing of exon 4 (performed to exclude S133T as a polymorphism, see above) did not detect V138F in 100 control alleles, confirming a previous study showing that this mutation is not a common polymorphism (17).

Both affected individuals of family C (C I-1 and C I-2) are also compound heterozygotes: They carry the mutation V138F as well as a 1151A-G (1375A-G) transition in exon 10 (E384G). DNA from their parents was not available for molecular studies. The clinically unaffected child (C II-1) is heterozygous for E384G.

The index patient in family D (D II-1) is homozygous for V138F as shown by direct sequencing. Whereas DNA of his father was not available, his mother, a maternal aunt, and a maternal uncle are heterozygous for V138F, and another maternal uncle is homozygous for the wild-type allele, as evidenced by both restriction enzyme digestion with Dde I (Fig. 3Go) and direct sequencing.

Haplotype analysis

Because the mutation V138F was found on at least one allele in the affected subjects of German origin (families B, C, and D), we compared the haplotypes of the available family members by genotyping five highly polymorphic dinucleotide repeat microsatellite markers in and around the PDS gene. V138F is associated with a common haplotype in the three families for markers within and close to the PDS gene, D7S2420, D7S496, and D7S2459 (Fig. 2Go). Haplotype sharing extends to marker D7S2456, located 0.22 Mbp from the PDS gene, in families B and D and possibly also in family C (Fig. 2Go).

The affected child in family A (A II-1, S133T) is homozygous at markers D7S2420 [4], D7S2456 [5], and the intragenic marker D7S2459 [6]. Therefore, his haplotype [4/5/6] is different from the V138F-associated haplotype [2/3/3]. His parents are both heterozygous for the S133T-associated allele but have different wild-type alleles (data not shown).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
We here report the PDS gene analysis in four families with Pendred’s syndrome. Four different PDS gene mutations are described, all of whom have been found in at least one Pendred’s syndrome family before: S133T (25), V138F (11, 17, 20, 22), Y530H (17, 22), and E384G (17, 24).

A missense mutation (leading to S133T) was found in family A. This mutation, located in the putative second transmembrane domain of pendrin (4), has recently been reported in a patient from Italy with Pendred’s syndrome (25). In addition to this earlier report, several lines of evidence suggest that S133T is a disease-causing mutation and not a polymorphism. The mutation is present in homozygous state in the affected child (A II-1), whereas both his unaffected parents are heterozygous, a finding consistent with autosomal-recessive transmission. In addition, S133 is conserved between PDS and his closest homologs in man (the diastrophic dysplasia gene DTDST and the down-regulated in adenoma gene DRA), mouse (mouse sulfate transporter), and rat (rat sulfate anion transporter 1, SAT1), suggesting that this residue is functionally important (32). This hypothesis is supported by the fact that the amino acid motif GTSRH (residues 131–135 in PDS) is completely conserved in the five related genes (4). S133 is also conserved between the PDS genes of man, mouse, and rat (6). Finally, the mutation is not present in 100 chromosomes from healthy control subjects and is therefore not a common polymorphism.

All five affected individuals belonging to the three German families with Pendred’s syndrome carry the mutation V138F on at least one allele, either in homozygous state (D II-1) or as a compound heterozygous mutation with Y530H (B II-1 and B II-2) or E384G (C I-1 and C I-2). We are not aware of common ancestors for these families originating from different regions in Germany. To distinguish between a de novo mutation (V138 being a mutational hot spot) and a common founder, we genotyped five highly polymorphic microsatellite markers from the PDS region. All affected persons share a common haplotype at three microsatellite loci. Because the investigated markers are highly polymorphic, the existence of a common haplotype in the general population is very unlikely. We therefore concluded that a founder effect accounts for the high frequency of V138F in our sample of German Pendred’s syndrome families. Founder effects have also been postulated for other PDS mutations, i.e. 1421delT (4), L236P and T416P (17, 20), E384G, and the donor splice site mutation 1001 + 1 G-A (17).

V138F has been shown to lead to mislocalization of pendrin in mammalian cell lines: Instead of appropriate trafficking to the plasma membrane, the mutant pendrin is retained within the endoplasmic reticulum. Therefore, the mutant protein has no ability to transport iodide across the cellular membrane (33). V138F has been reported in four other patients with Pendred’s syndrome: a familial (22) and isolated patient (17) whose ethnic origins were not stated, a patient from Belgium (20) and a Mexican patient (11). It is not known whether this mutation is common in Western Europe and Germany. Because we found it in homozygous or compound heterozygous state in three German families, we speculate that V138F is a frequent PDS mutation in the German population. Although some German subjects may have been analyzed for PDS mutations (17), no detailed information is available whether V138F has been identified in this population before. If V138F was frequent in the German population, a simple diagnostic test using the restriction endonuclease Dde I would constitute a first step in the molecular diagnosis of Pendred’s syndrome. In other populations different PDS gene mutations occur frequently (e.g. H723R in Japanese patients with Pendred’s syndrome or large vestibular aqueduct) (21, 27). Therefore, it is conceivable that a region-specific screening test for specific populations could be developed to facilitate the rapid identification of PDS mutations, especially in patients with Pendred’s syndrome who do not present with the typical phenotype. However, we are aware of the large number of PDS mutations affecting almost all regions of the gene. Further large studies are therefore needed to clarify whether V138F is a frequent mutation in the German population.

Founder mutations are more commonly found in isolated populations (34) such as the Finish population (35) or Ashkenazi Jews. However, there are a few reports of founder effects in the German population as for example in the BRCA1/BRCA2 (36), SCA6 (37), and VHL (38) genes causing familial breast and ovarian cancer, spinocerebellar ataxia type 6, and von Hippel Lindau disease, respectively. This report is another example of a founder mutation in the German population.

Both alleles of the affected homozygous Turkish child (A II-1) harboring the mutation S133T had an identical haplotype. This suggests that the parents may have a distant common ancestor. Further studies comparing the haplotypes of different individuals with S133T (25) should clarify whether S133T is also a founder mutation.

In only one of our patients was a perchlorate discharge test performed. The combination of sensorineural hearing loss, goiter, and positive perchlorate discharge test is characteristic of Pendred’s syndrome. In the absence of perchlorate discharge tests, we considered the diagnosis of Pendred’s syndrome in subjects with sensorineural hearing loss associated with enlarged vestibular aqueduct, thyroid dysfunction, and/or goiter. It should especially be kept in mind that there are several reports of false-negative perchlorate discharge tests in patients with Pendred’s syndrome in whom the diagnosis was confirmed by DNA analysis (12, 15, 19, 20, 28). This might in part be due to the fact that perchlorate discharge tests are not performed in a well-standardized fashion and influenced by external factors such as iodine intake. We propose to analyze the PDS gene in every patient presenting with symptoms of Pendred’s syndrome. Because DNA analysis of the PDS gene is a rapid, noninvasive, and reliable test, it may replace the discharge test as a diagnostic procedure. Pendred’s syndrome is also a rare differential diagnosis in newborns with a positive TSH screening result as shows the example of patients B II-1 and D II-1 (3, 39).

In summary, we report the molecular genetic analysis of the PDS gene in six patients with Pendred’s syndrome from four different families. In each patient the genetic cause for the disease was elucidated. Finally, we show that one of the detected mutations (V138F) occurs on at least one allele of all affected individuals from Germany investigated and this likely is due to a founder effect.


   Acknowledgments
 
We are grateful to Dr. Samuel Refetoff (University of Chicago, Chicago, IL) for review of the manuscript. Furthermore, we thank the families for their participation in the study.


   Footnotes
 
This work was supported by the University of Mainz (MAIFOR).

Abbreviations: CT, Computed tomography; MRI, magnetic resonance imaging; PDS, Pendred’s syndrome gene.

Received August 20, 2002.

Accepted February 27, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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