title: 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.
abstract: 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.
  
  
  METHODS
  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 (1226G>A, R409H) and for a novel 11 bp duplication (1561_1571CTTGGAATGGC, S523fsX548). The latter mutation creates a frame shift 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.
authors.affiliation: Department of Medical Sciences, University of Milan, Milan, Italy. l.fugazzola@policlinico.mi.it
authors.forename: Laura
authors.initials: L
authors.lastname: Fugazzola
authors.forename: Valentina
authors.initials: V
authors.lastname: Cirello
authors.forename: Silvia
authors.initials: S
authors.lastname: Dossena
authors.forename: Simona
authors.initials: S
authors.lastname: Rodighiero
authors.forename: Marina
authors.initials: M
authors.lastname: Muzza
authors.forename: Pierangela
authors.initials: P
authors.lastname: Castorina
authors.forename: Faustina
authors.initials: F
authors.lastname: Lalatta
authors.forename: Umberto
authors.initials: U
authors.lastname: Ambrosetti
authors.forename: Paolo
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: Guido
authors.initials: G
authors.lastname: Bottà
authors.forename: Markus
authors.initials: M
authors.lastname: Paulmichl
mesh_terms: D000328:Adult; D017668:Age of Onset; D000595:Amino Acid Sequence; D001483:Base Sequence; D002460:Cell Line; D007758:Ear, Inner / Q000000981:diagnostic imaging; D005192:Family Health; D005260:Female; D014644:Genetic Variation; D006319:Hearing Loss, Sensorineural / Q000000981:diagnostic imaging / Q000235:genetics*; D006579:Heterozygote; D006801:Humans; D007668:Kidney / Q000166:cytology; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics*; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D010641:Phenotype; D011859:Radiography; D000076988:Sulfate Transporters
chemical_list: D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters