Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene

Napiontek, Ulrike; Borck, Guntram; Müller-Forell, Wiebke; Pfarr, Nicole; Bohnert, Andrea; Keilmann, Annerose; Pohlenz, Joachim

doi:10.1210/jc.2004-1013

Cited by 26 publications

(30 citation statements)

References 33 publications

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“…However the analysis could be started with exons 4, 10, 14 and 11 + 12, where we found the majority of pathogenic mutations. The most common mutation in our cohort, p.Val138Phe (18% of all pathogenic alleles), was also found in some familial cases in Germany (Borck et al, 2003) and was shown to be a founder mutation in the Central European area as was the mutation p.Thr416Pro (found twice -5.9% -in our study) also described in Germany (Napiontek et al, 2004).…”

Section: Spectrum Of the Slc26a4 Mutationssupporting

confidence: 73%

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

Pourová

Janoušek²,

Jurovčík³

et al. 2010

Annals of Human Genetics

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SummaryMutations in SLC26A4 cause Pendred syndrome (PS) -hearing loss with goitre -or DFNB4 -non-syndromic hearing loss (NSHL) with inner ear abnormalities such as Enlarged Vestibular Aqueduct (EVA) or Mondini Dysplasia (MD). We tested 303 unrelated Czech patients with early hearing loss (298 with NSHL and 5 with PS), all GJB2-negative, for SLC26A4 mutations and evaluated their clinical and radiological phenotype. Among 115 available HRCT/MRI scans we detected three MD (2.6%), three Mondini-like affections (2.6%), 16 EVA (13 bilateral -19.2% and 15.6% respectively) and 61 EVA/MD-negative scans (73.4%). We found mutation(s) in 26 patients (8.6%) and biallelic mutations in eight patients (2.7%) out of 303 tested. In 18 of 26 (69%) patients, no second mutation could be detected even using MLPA. The spectrum of SLC26A4 mutations in Czech patients is broad without any prevalent mutation. We detected 21 different mutations (four novel). The most frequent mutations were p.Val138Phe and p.Leu445Trp (18% and 8.9% of pathogenic alleles respectively). Among 13 patients with bilateral EVA, six patients (50%) carry biallelic mutations. In EVA -negative patients no biallelic mutations were found but 4.9% had monoallelic mutations. SLC26A4 mutations are present mostly in patients with EVA/MD and/or progressive HL and those with affected siblings.

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Section: Spectrum Of the Slc26a4 Mutationssupporting

confidence: 73%

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

Pourová

Janoušek²,

Jurovčík³

et al. 2010

Annals of Human Genetics

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“…Intrafamilial and interfamilial phenotypic variability, mostly in terms of presence/absence and severity of thyroid and inner ear malformations, have been reported by other groups (12)(13)(14)32). In the family tested in the present work, the extreme variability can not only be found in the degree of hearing impairment, but also in the time of onset for the thyroid alterations.…”

Section: Discussionmentioning

confidence: 58%

“…Mutations of this gene have been associated, in compound heterozygosity or in homozygosity, with Pendred syndrome (PS), an autosomal recessive disorder first described in 1896 and characterized by the association of sensorineural hearing loss (SNHL) and goiter (10). The phenotype of PS is highly variable with regard to deafness, goiter, and thyroid function (12)(13)(14)(15). Sensorineural deafness is congenital, and in most cases has a progressive course.…”

Section: Introductionmentioning

confidence: 99%

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

et al. 2007

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Objective: Pendred syndrome (PS) is characterized by the association of sensorineural hearing loss (SNHL) and a partial iodide organification defect at the thyroid level. It is caused by mutations in the SLC26A4 gene. The encoded transmembrane protein, called pendrin, has been found to be able to transport chloride and other anions. Design: The aim of the present study was to characterize a family with PS, which shows a strong intrafamilial phenotypic variability, including kidney atrophy in one member. The age of disease-onset was significantly different in all three affected siblings, ranging from 2 to 21 years for thyroid alterations and from 1.5 to 11 years for SNHL. Methods: Clinical and genetic studies were carried out in affected siblings. The functional activity of the novel duplication found was studied by a fluorimetric method in a human renal cell line (HEK293 Phoenix) in which the protein was overexpressed. Results: All three siblings were found to be compound heterozygotes for the missense mutation (1226GOA, R409H) and for a novel 11 bp duplication (1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frameshift leading to the loss of the entire carboxy-terminus domain. Functional studies of this mutant demonstrated impaired transport of chloride and iodide when expressed in HEK 293 Phoenix cells, when compared with wild type pendrin. Conclusions: A novel 11 bp duplication was found in a family with Pendred syndrome, showing a high intrafamilial phenotypic variability. An impaired transmembrane anionic transport of the mutated SLC26A4 protein was demonstrated in functional studies using a heterologous cell system.

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“…P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4)(5)(6)(7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791).…”

mentioning

confidence: 99%

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

Pera

Dossena

Rodighiero³

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

105

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Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.ion transport physiology ͉ genotype-phenotype correlation P endred syndrome (PS) (OMIM#274600) (1) is an autosomal recessive disorder characterized by sensorineural hearing loss (SNHL) and malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) (2) to Mondini malformation (3), combined with deficient iodide organification in the thyroid gland, as demonstrated by the positive perchlorate discharge test in affected individuals (4-7). Another form of SNHL associated with EVA, however, showing normal thyroid function, is called nonsyndromic EVA (ns-EVA) (OMIM#600791). The clinical features of PS are the consequence of impaired pendrin function (1), a protein encoded by the SLC26A4 gene (NM 000441). It is a member of the multifunctional anion transporter family SLC26, which mediates the exchange of anions including Cl Ϫ , HCO 3 Ϫ , OH Ϫ , I Ϫ , or formate (8). Pendrin seems to be responsible for the efflux of iodide in thyrocytes (9-11), and for mediating Cl Ϫ /HCO 3 Ϫ exchange in the kidney cortex (12) and inner ear. In the latter, pendrin is involved in the conditioning of endolymphatic fluid, presumably because of HCO 3 Ϫ secretion (13), thereby modifying inner ear acid-base homeostasis. A variable feature of PS is the development of goitre (apparent in only about 50% of the affected individuals). At the thyroid level, the role of pendrin is not conclusive. The transporter could act as an iodide transporter at the apical membrane of thyroid cells and impaired function could therefore lead to the iodide organification defect observed in PS patients (10,11,(14)(15)(16). PS seems to be linked to bi-allelic mutations of the SLC26A4 genes. ns-EVA is genetically more heterogeneous relative to PS, and a...

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Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene

Cited by 26 publications

References 33 publications

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

Spectrum and Frequency of SLC26A4 Mutations Among Czech Patients with Early Hearing Loss with and without Enlarged Vestibular Aqueduct (EVA)

High phenotypic intrafamilial variability in patients with Pendred syndrome and a novel duplication in the SLC26A4 gene: clinical characterization and functional studies of the mutated SLC26A4 protein

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA

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