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

Fugazzola, Laura; Cirello, Valentina; Dossena, Silvia; Rodighiero, Simona; Muzza, Marina; Castorina, Pierangela; Lalatta, Faustina; Ambrosetti, Umberto; Beck‐Peccoz, Paolo; Botta, Guido Fernando; Paulmichl, Markus

doi:10.1530/eje-07-0263

Cited by 32 publications

(40 citation statements)

References 41 publications

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“…These data are indicative of a facilitated iodide transport (a more detailed description of the technique is given in Methods and SI Materials and Methods). The transport values (⌬Fmax%) of WT pendrin described in this study are similar to those described earlier (20).…”

Section: Slc26a4 Three Of Them (F354s L597ssupporting

confidence: 88%

“…Moreover, the transformation of two allelic variants (V88I and L597S) that were not functionally different compared to WT SLC26A4, into mutations fitting the proline/fixed charge role (i.e., V88P and L597P), resulted in the annihilation of transport activity. Although, it is important to note that mutations that do not enter into this proline/fixed charge role can be functionally detrimental or without functional implication (15,20,21,26,27). In these cases, only functional tests can unambiguously distinguish between different SLC26A4 gene mutations in SNPs and those mutations that actually cause a reduced function and ultimately disease symptoms.…”

Section: Discussionmentioning

confidence: 99%

“…To assay the transport function of the SLC26A4 allelic variants, we used a recently described fast fluorometric method for measuring chloride/iodide (Cl Ϫ /I Ϫ ) transport (19,20). With this technique, SLC26A4-mediated anion flux is measured by monitoring I Ϫ -and Cl Ϫ -induced quenching of an enhanced-yellow fluorescent protein (EYFP) fluorescence signal (19).…”

Section: Slc26a4 Three Of Them (F354s L597smentioning

confidence: 99%

“…The fluorometric method was described previously in detail (19,20). In brief, the SLC26A4 protein is able to transport chloride (19,29,30) as well as iodide (11,15,27,31,32), and therefore, because the EYFP protein is a fluorescent dye sensitive to intracellular halides, this dye is particularly suitable for sensing changes in the intracellular chloride as well as iodide amount, and therefore to measure the respective ion fluxes across the cell membrane.…”

Section: Subjectsmentioning

confidence: 99%

“…In this study, we screened the SLC26A4 coding sequence in a cohort of normal hearing controls. Using the fast fluorometric method for measuring Cl Ϫ /I Ϫ transport via pendrin as described earlier (19,20), we performed functional analyses on one mutant in the SLC26A4 protein found only in our control cohort (L597S), as well as on nine mutants found in our cohort of controls or patients suffering from PS or ns-EVA (18). To further examine the SLC26A4 structure/function relationship, we also tested two in silico designed mutations.…”

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confidence: 99%

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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.

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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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Section: Slc26a4 Three Of Them (F354s L597ssupporting

confidence: 88%

Section: Discussionmentioning

confidence: 99%

Section: Slc26a4 Three Of Them (F354s L597smentioning

confidence: 99%

Section: Subjectsmentioning

confidence: 99%

mentioning

confidence: 99%

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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.

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105

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Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

et al. 2018

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Due to the high genetic heterogeneity of hearing loss, current clinical testing includes sequencing large numbers of genes, which often yields a significant number of novel variants. Therefore, the standardization of variant interpretation is crucial to provide consistent and accurate diagnoses. The Hearing Loss Variant Curation Expert Panel was created within the Clinical Genome Resource to provide expert guidance for standardized genomic interpretation in the context of hearing loss. As one of its major tasks, our Expert Panel has adapted the ACMG/AMP guidelines for the interpretation of sequence variants in hearing loss genes. Here, we provide a comprehensive illustration of the newly specified ACMG/AMP hearing loss rules. Three rules remained unchanged, four rules were removed, and the remaining twenty-one rules were specified. These rules were further validated and refined using a pilot set of 51 variants assessed by curators and expert opinion. Of the 51 variants evaluated in the pilot, 37% (19/51) changed category based upon application of the expert panel specified rules and/or aggregation of evidence across laboratories. These hearing loss-specific ACMG/AMP rules will help standardize variant interpretation, ultimately leading to better care for individuals with hearing loss.

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Intrafamilial phenotypic variability in families with biallelic SLC26A4 mutations

et al. 2013

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The possibility of variability concerning auditory phenotype should be considered even within family members carrying the same SLC26A4 mutations when providing genetic counseling to multiplex EVA families. Mutations in the currently known genes associated with EVA other than SLC26A4 were not found to be responsible for the intrafamilial phenotypic variability. Modifier genes or environmental factors other than the currently known genes seem to play a role in the phenotypic expressions of EVA patients.

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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

Cited by 32 publications

References 41 publications

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

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

Expert specification of the ACMG/AMP variant interpretation guidelines for genetic hearing loss

Intrafamilial phenotypic variability in families with biallelic SLC26A4 mutations

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