title: Iodide transport defect: functional characterization of a novel mutation in the Na+/I- symporter 5'-untranslated region in a patient with congenital hypothyroidism.
abstract: BACKGROUND
  Iodide transport defect (ITD) is an autosomal recessive disorder caused by impaired Na(+)/I(-) symporter (NIS)-mediated active iodide accumulation into thyroid follicular cells. Clinical manifestations comprise a variable degree of congenital hypothyroidism and goiter, and low to absent radioiodide uptake, as determined by thyroid scintigraphy. Hereditary molecular defects in NIS have been shown to cause ITD.
  
  
  OBJECTIVE
  Our objective was to perform molecular studies on NIS in a patient with congenital hypothyroidism presenting a clinical ITD phenotype.
  
  
  METHODS
  The genomic DNA encoding NIS was sequenced, and an in vitro functional study of a newly identified NIS mutation was performed.
  
  
  RESULTS
  The analysis revealed the presence of an undescribed homozygous C to T transition at nucleotide -54 (-54C>T) located in the 5'-untranslated region in the NIS sequence. Functional studies in vitro demonstrated that the mutation was associated with a substantial decrease in iodide uptake when transfected into Cos-7 cells. The mutation severely impaired NIS protein expression, although NIS mRNA levels remained similar to those in cells transfected with wild-type NIS, suggesting a translational deficiency elicited by the mutation. Polysome profile analysis demonstrated reduced levels of polyribosomes-associated mutant NIS mRNA, consistent with reduced translation efficiency.
  
  
  CONCLUSIONS
  We described a novel mutation in the 5'-untranslated region of the NIS gene in a newborn with congenital hypothyroidism bearing a clinical ITD phenotype. Functional evaluation of the molecular mechanism responsible for impaired NIS-mediated iodide concentration in thyroid cells indicated that the identified mutation reduces NIS translation efficiency with a subsequent decrease in protein expression and function.
authors.affiliation: Centro de Investigaciones en Bioquímica Clínica e Inmunología-Consejo Nacional de Investigaciones Científicas y Técnicas, Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Haya de la Torre y Medina Allende, 5000 Córdoba, Argentina.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Nicola
authors.forename: Magalí
authors.initials: M
authors.lastname: Nazar
authors.forename: Caroline
authors.initials: C
authors.lastname: Serrano-Nascimento
authors.forename: Francemilson
authors.initials: F
authors.lastname: Goulart-Silva
authors.forename: Gabriela
authors.initials: G
authors.lastname: Sobrero
authors.forename: Graciela
authors.initials: G
authors.lastname: Testa
authors.forename: Maria Tereza
authors.initials: MT
authors.lastname: Nunes
authors.forename: Liliana
authors.initials: L
authors.lastname: Muñoz
authors.forename: Mirta
authors.initials: M
authors.lastname: Miras
authors.forename: Ana María
authors.initials: AM
authors.lastname: Masini-Repiso
mesh_terms: D020121:5' Untranslated Regions; D003409:Congenital Hypothyroidism / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D027981:Symporters / Q000235:genetics*; D000099209:Sodium-Iodide Symporters
chemical_list: D020121:5' Untranslated Regions; D027981:Symporters; D000099209:Sodium-Iodide Symporters