title: Molecular and functional studies of 4 candidate loci in Pendred syndrome and nonsyndromic hearing loss.
abstract: Patients with PS or non-syndromic deafness were submitted to genetic/functional analyzes of SLC26A4, of its binding domain for FOXI1 (FOXI1-DBD), of the transcription activator FOXI1, and of the potassium channel KCNJ10. SLC26A4 was the most frequently mutated gene. An altered intracellular localization with immunocytochemistry, and a hampered maturation process were demonstrated for two novel SLC26A4 variants. Biochemical and immunocytochemical analyzes led to the development of a more sensitive fluorometric functional assay able to reveal the partial loss-of-function of SLC26A4 mutations. A novel missense variant was found in FOXI1 gene, though functional analysis showed no significant impairment in the transcriptional activation of SLC26A4. Finally, 3 patients were found to harbor a variant in KCNJ10, which was classified as polymorphism. The novelty of the study resides in the analysis of all the 4 candidate genetic loci linked to PS/non-syndromic deafness, and in the precise definition of the thyroid phenotype. PS was invariably associated with biallelic mutations of SLC26A4, whereas the genetic origin of non-syndromic deafness remained largely undetermined, since monoallelic SLC26A4 variants accounted for one fourth of the cases and FOXI1 and KCNJ10 were not involved in this series.
authors.affiliation: Dept. of Medical Sciences, Università degli Studi, Milan, Italy.
authors.forename: Valentina
authors.initials: V
authors.lastname: Cirello
authors.forename: Claudia
authors.initials: C
authors.lastname: Bazzini
authors.forename: Valeria
authors.initials: V
authors.lastname: Vezzoli
authors.forename: Marina
authors.initials: M
authors.lastname: Muzza
authors.forename: Simona
authors.initials: S
authors.lastname: Rodighiero
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.forename: Antonia
authors.initials: A
authors.lastname: Maffini
authors.forename: Guido
authors.initials: G
authors.lastname: Bottà
authors.forename: Luca
authors.initials: L
authors.lastname: Persani
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Giuliano
authors.initials: G
authors.lastname: Meyer
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
mesh_terms: D000293:Adolescent; D000328:Adult; D000483:Alleles; D000818:Animals; D019556:COS Cells; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D002522:Chlorocebus aethiops; D005260:Female; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014644:Genetic Variation; D005838:Genotype; D006044:Goiter, Nodular / Q000235:genetics*; D006319:Hearing Loss, Sensorineural / Q000235:genetics*; D006801:Humans; D007223:Infant; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D024661:Potassium Channels, Inwardly Rectifying / Q000235:genetics*; D000076988:Sulfate Transporters; D015533:Transcriptional Activation; D055815:Young Adult; D000098854:Kcnj10 Channel
chemical_list: C477894:FOXI1 protein, human; D051858:Forkhead Transcription Factors; D000098854:Kcnj10 Channel; D026901:Membrane Transport Proteins; D024661:Potassium Channels, Inwardly Rectifying; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters