Two Frequent Missense Mutations in Pendred Syndrome

Hauwe, P. van; Everett, Lorraine A.; Coucke, Paul; Scott, Daryl A.; Kraft, Michelle L.; Ris‐Stalpers, Carrie; Bolder, C.H.H.M.; Otten, Barto J.; Vijlder, J. de; Dietrich, Nicole; Ramesh, A.; Srisailapathy, S.; Parving, Agnete; Cremers, C.W.R.J.; Willems, P. J.; Smith, Richard J.H.; Green, E.D.; Camp, Guy Van

doi:10.1093/hmg/7.7.1099

Cited by 166 publications

(105 citation statements)

References 11 publications

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“…These data are consistent with the phenotype observed in the respective patients. The missense mutation R409H has been associated with PS in several cohorts and has been shown to impair pendrin function (28)(29)(30)(31), in agreement with the phenotype resulting from the compound heterozygosis described in the affected members.…”

Section: Discussionsupporting

confidence: 66%

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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Section: Discussionsupporting

confidence: 66%

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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“…Even though this occurs in other populations, the four mutations most commonly detected among Caucasian patients are not very frequent (p.T416P and c.1001 þ 1G4A) or do not appear in our Spanish population (p.E384G and p.L236P). 12,14 The mutational spectrum in Spain is similar to those of the Italian and French populations, sharing 12 of the SLC26A4 alleles with the French 13 and four with the Italian population. 15 However, in our population the most frequent mutation is the novel p.Q514K found in six alleles (17%) that derives from a common founder.…”

Section: Discussionmentioning

confidence: 76%

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

et al. 2008

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Pendred syndrome (PS) and DFNB4, a non-syndromic sensorineural hearing loss with enlargement of the vestibular aqueduct (EVA), are caused by mutations in the SLC26A4 gene. Both disorders are recessive, and yet only one mutated SLC26A4 allele, or no mutations, are identified in many cases. Here we present the genetic characterization of 105 Spanish patients from 47 families with PS or non-syndromic EVA and 20 families with recessive non-syndromic hearing loss, which segregated with the DFNB4 locus. In this cohort, two causative SLC26A4 mutations could be characterized in 18 families (27%), whereas a single mutated allele was found in a patient with unilateral hearing loss and EVA in the same ear. In all, 24 different causative mutations were identified, including eight novel mutations. The novel p.Q514K variant was the most prevalent mutation in SLC26A4, accounting for 17% (6/36) of the mutated alleles identified in this study, deriving from a founder effect. We also characterized a novel multiexon 14 kb deletion spanning from intron 3 to intron 6 (g.8091T_22145Cdel). This study also revealed the first case of a de novo recessive mutation p.Q413P causing PS that arose in the proband's paternal allele, the maternal one carrying the p.L445W. The relevance of our results for genetic diagnosis of PS and non-syndromic EVA hearing loss is discussed.

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“…The most frequent mutations in Czech patients are p.Val138Phe and p.Leu445Trp, identified in six and three patients respectively (18% and 8.9% of all mutant alleles). Remaining mutations were found only once or twice each (representing 5.9% or 2.9% of all mutant alleles respectively) -see Table 3 (Coyle et al, 1998;Van Hauwe et al, 1998;Usami et al, 1999;Adato et al, 2000;Campbell et al, 2001;Park et al, 2003;Blons et al, 2004;Prasad et al, 2004;Pryor et al, 2005;Propst et al, 2006). Parents (or descendants in cases 3830 and 4745) of all patients with two pathogenic mutations were subsequently tested and mutations were found in the heterozygous state in all of them, confirming their independent segregation.…”

Section: Spectrum and Frequency Of Mutationsmentioning

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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Two Frequent Missense Mutations in Pendred Syndrome

Cited by 166 publications

References 11 publications

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

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

A mutational analysis of the SLC26A4 gene in Spanish hearing-impaired families provides new insights into the genetic causes of Pendred syndrome and DFNB4 hearing loss.

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

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