Functional assessment of allelic variants in the <i>SLC26A4</i> gene involved in Pendred syndrome and nonsyndromic EVA
-
- Alejandra Pera
- Unidad de Genética Molecular, Hospital Ramón y Cajal, Centro de Investigación Biomédica de Enfermedades Raras, ISCIII, 28034 Madrid, Spain;
-
- Silvia Dossena
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, A-5020 Salzburg, Austria; and
-
- Simona Rodighiero
- Centro Interdisciplinare Materiali e Interfacce Nanostrutturati and
-
- Marta Gandía
- Unidad de Genética Molecular, Hospital Ramón y Cajal, Centro de Investigación Biomédica de Enfermedades Raras, ISCIII, 28034 Madrid, Spain;
-
- Guido Bottà
- Department of Biomolecular Sciences and Biotechnology, Università degli Studi di Milano, 20122 Milan, Italy
-
- Giuliano Meyer
- Department of Biomolecular Sciences and Biotechnology, Università degli Studi di Milano, 20122 Milan, Italy
-
- Felipe Moreno
- Unidad de Genética Molecular, Hospital Ramón y Cajal, Centro de Investigación Biomédica de Enfermedades Raras, ISCIII, 28034 Madrid, Spain;
-
- Charity Nofziger
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, A-5020 Salzburg, Austria; and
-
- Concepción Hernández-Chico
- Unidad de Genética Molecular, Hospital Ramón y Cajal, Centro de Investigación Biomédica de Enfermedades Raras, ISCIII, 28034 Madrid, Spain;
-
- Markus Paulmichl
- Institute of Pharmacology and Toxicology, Paracelsus Medical University, A-5020 Salzburg, Austria; and
抄録
<jats:p> 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 <jats:italic>SLC26A4</jats:italic> 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 <jats:italic>SLC26A4</jats:italic> variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the <jats:italic>SLC26A4</jats:italic> 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. </jats:p>
収録刊行物
-
- Proceedings of the National Academy of Sciences
-
Proceedings of the National Academy of Sciences 105 (47), 18608-18613, 2008-11-25
Proceedings of the National Academy of Sciences