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Identification of Two Diverent Mutations in the PDS Gene in an Inbred

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Identification of Two Diverent Mutations in the PDS Gene in an Inbred J Med Genet 1999;36:475–477 475 Identification of two diVerent mutations in the J Med Genet: first published as 10.1136/jmg.36.6.475 on 1 June 1999. Downloaded from PDS gene in an inbred family with Pendred syndrome P J Coucke, P Van Hauwe, L A Everett, O Demirhan, Y Kabakkaya, N L Dietrich, R J H Smith, E Coyle, W Reardon, R Trembath, P J Willems, E D Green, G Van Camp Abstract discharge test,2 an abnormally developed coch- Department of Recently the gene responsible for Pendred lea (Mondini malformation), and a widened Medical Genetics, syndrome (PDS) was isolated and several vestibular aqueduct.34 In 1996, the Pendred University of Antwerp-UIA, mutations in the PDS gene have been syndrome gene was localised on chromosome Universiteitsplein 1, identified in Pendred patients. Here we 7q31, initially in a region of 5.5 cM.5 This 2610 Antwerp, Belgium report the occurrence of two diVerent region was then refined67 and, recently, the P J Coucke PDS mutations in an extended inbred Pendred syndrome gene (PDS) was isolated.8 P Van Hauwe Turkish family. The majority of patients in The gene encodes a transmembrane protein, P J Willems this family are homozygous for a splice G Van Camp named pendrin, that is closely related to known site mutation (1143-2A→G) aVecting the 3' sulphate transporters. The homology of pen- splice site consensus sequence of intron 7. Genome Technology drin to two other sulphate transporters impli- Branch, National However, two aVected sibs with non- Human Genome consanguineous parents are compound cated in human diseases, “down regulated in Research Institute, heterozygotes for the splice site mutation adenoma” (DRA) involved in congenital chlo- 9 National Institutes of and a missense mutation (1558T→G), ride diarrhoea, and a sulphate transporter Health, Bethesda, (DTD) involved in diastrophic dysplasia,10 Maryland 20892, USA substituting an evolutionarily conserved L A Everett amino acid. The latter mutation has been suggests that the sulphate transporter gene N L Dietrich found previously in two Pendred families family is clinically important. However, the E D Green originating from The Netherlands, indi- exact function of pendrin in the thyroid and its cating that the 1558T→G mutation may be involvement in cochlear development remain Department of a common mutation. to be elucidated. To date, 29 diVerent muta- Genetics, University of (J Med Genet 1999;36:475–477) Leicester, Adrian tions in the PDS gene have been reported in 81112 Building, Leicester Pendred syndrome patients. Four PDS Keywords: PDS gene; Pendred syndrome LEI7RH, UK mutations are found to be recurrent, at least in E Coyle the western European population (L236P, http://jmg.bmj.com/ R Trembath 11 12 Pendred syndrome (MIM 274600) is an auto- E384G, T416P, and 1001+1G→Á). Inter- Division of Clinical somal recessive disorder with an estimated fre- familial as well as intrafamilial clinical variabil- Genetics and Fetal quency of 1-8 per 100 000 characterised by ity has been described in Pendred syndrome13 Medicine, Institute of prelingual deafness and goitre.1 Additional and recently a PDS mutation has been Child Health, abnormalities are an iodide organification reported in a family with non-syndromic reces- University of London, 14 UK defect that can be shown by the perchlorate sive deafness. W Reardon on September 24, 2021 by guest. Protected copyright. I Department of Otolaryngology, University of Iowa II Hospital, Iowa City, USA R J H Smith III Department of Medical Biology, IV AB Faculty of Medicine, University of Cukurova, 01330 V Balcali-Adana, Turkey 23 5 101112 14 15 19 20 O Demirhan Department of Otolaryngology, Orta Dogu Private Hospital, CD Adana, Turkey Y Kabakkaya VI 1234567 11 14 15 Correspondence to: Dr Van Camp. Received 27 August 1998 Revised version accepted for Figure 1 Pedigree of the inbred Pendred syndrome family. Only family members from whom DNA was obtained are publication 15 December numbered. Black bars beneath subjects represent the 1143-2A→G mutation, striped bars represent the 1558T→G 1998 mutation, and white bars represent wild type alleles. 476 Coucke, Van Hauwe, Everett, et al J Med Genet: first published as 10.1136/jmg.36.6.475 on 1 June 1999. Downloaded from http://jmg.bmj.com/ Figure 2 Sequence analysis of the region flanking the 1143-2A→G and the 1558T→G mutations. The arrows point to the variant nucleotide. (A) To illustrate the 1143-2A→G mutation, the sequence from control DNA, a compound heterozygote, and a homozygote for the mutation are shown. (B) To illustrate the 1558T→G mutation, the sequence from a control and a compound heterozygote are shown. Here we report two diVerent PDS muta- To identify the PDS mutations in this family, tions, one novel and one previously reported, DNA from two patients (V.2 and VI.3) of the on September 24, 2021 by guest. Protected copyright. segregating in an extended inbred Pendred pedigree (fig 1) was analysed. Patient V.2, a syndrome family originating from a small and member of consanguineous branch A, was isolated Turkish village.6 The family includes expected to be homozygous for a PDS more than 13 aVected subjects, all having mutation, whereas patient VI.3, whose parents prelingual hearing loss and a palpable goitre.15 are not consanguineous, was expected to be a In a previous study, linkage analysis with mark- compound heterozygote (assuming the pres- ers flanking the PDS gene showed two different ence of two diVerent mutations). disease haplotypes.6 Six aVected subjects, all Mutation detection of the PDS gene was with consanguineous parents, were homo- performed by direct sequencing of PCR prod- zygous for the closest flanking markers, ucts using the ABI PRISMTM BigDyeTM Termi- whereas two patients with non-consanguineous nator Cycle Sequencing Ready Reaction Kit parents were heterozygous. Several possibilities (Perkin Elmer, Foster City, CA). Genomic could explain these results. Firstly, two diVer- DNA was used as template for PCR amplifica- ent mutations segregating on distinct haplo- tion of DNA segments containing the PDS types could be responsible for Pendred syn- exons, as described previously.8 A homozygous drome in this family. Secondly, a single A to G substitution was observed at the 3' mutation could be responsible for Pendred splice site of intron 7 (1143-2A→G) in patient syndrome, originating from a very distant V.2 (fig 2A). Patient VI.3 was found to be a common ancestor and with diVerent haplo- compound heterozygote for this splice site types evolving from numerous recombinations. mutation andaTtoGsubstitution at position A third possibility is the independent occur- 1558 in exon 11 (1558T→G) (fig 2B). rence of the same mutation on distinct Linkage analysis in this family showed that haplotypes, perhaps as the result of a mutation the 1143-2A→G mutation segregated with hot spot. Pendred syndrome. All the patients from the Two d i V erent mutations in the PDS gene 477 consanguineous branches of the family were reported for several other disorders,17–19 and it homozygous for this mutation (fig 1), whereas has been suggested that multiple mutations in a J Med Genet: first published as 10.1136/jmg.36.6.475 on 1 June 1999. Downloaded from the two patients in branch C (VI.3 and VI.6) single gene may be a relatively common were heterozygous. As the 1143-2A→G muta- phenomenon in inbred communities.20 tion changes a 100% conserved nucleotide of The identification of two diVerent mutations the 3' splice site consensus sequence,16 the in this consanguineous family indicates that mutation most probably aVects splicing of the great care should be taken when inbred PDS gene. However, as the PDS gene is only families of this type are used for linkage analy- expressed in thyroid, kidney, and brain,8 and as sis by homozygosity mapping. none of these tissues was available from this family, we were unable to analyse the eVect of This study was supported by a grant from the University of Antwerp, a grant from the Flemish Fonds voor Wetenschap- the mutation at the mRNA level. Even with pelijk Onderzoek (FWO), and by NIH grant R01DCO2842 nested PCR, we failed to amplify fragments of (RJHS). PVH holds a predoctoral research position with the Vlaams Instituut ter Bevordering van het Wetenschappelijk- the PDS gene from EBV transformed B cells Technologisch onderzoek in de industrie (IWT). GVC holds a (data not shown). research position with the FWO. Financial support for this work The presence of the 1558T→G mutation was from the MRC and Action Research. was analysed by sequence analysis in branch C, 1 Pendred V. Deaf mutism and goitre. Lancet 1896;ii:532. the non-consanguineous part of the pedigree 2 Illum P, Kiaer HW, Hansen JH, Sondergaard G. Fifteen (fig 1), and found to be present in patients VI.3 cases of Pendred’s syndrome, congenital deafness with spo- radic goiter. Arch Otolaryngol 1972;96:297-304. and VI.6 and also in VI.7, which is consistent 3 Cremers CWRJ, Bolder CH, Adimiraal RJC, et al. Progres- sive sensorineural hearing loss and a widened vestibular with the previously described haplotype aqueduct in Pendred syndrome. 6 Arch Otolaryngol Head analysis. The mutation leads to the predicted Neck Surg 1998;124:501-5. substitution of Leu for Trp at position 445 of 4 Phelps PD, CoVey RA, Trembath RC, et al. Radiological malformations of the ear in Pendred syndrome. Clin Radiol the pendrin protein (L445W). Alignment of 1998;53:268-73. 5 Coyle B, CoVey R, Armour JA, et al. Pendred syndrome the PDS sequence with four other homologous (goitre and sensorineural hearing loss) maps to chromo- genes (human DRA, human DTD, mouse some 7 in the region containing the nonsyndromic deafness DTD, and rat sulphate anion transporter gene DFNB4.
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