title: Segregation of S292F TPO gene mutation in three large Tunisian families with thyroid dyshormonogenesis: evidence of a founder effect.
abstract: We aimed to identify causal mutation(s) in 13 patients with thyroid dyshormonogenesis (TD) from three consanguineous Tunisian families. A 12-year clinical follow-up showed phenotypic variability ranging from the presence to the absence of goiter, sensorineural deafness, and mental retardation. Genetic analysis using microsatellite markers within two candidate genes (TPO and PDS) gave evidence of linkage with the TPO gene. Sequencing of its 17 exons and their flanking intron-exon junctions revealed the previously described c.875C>T (p.S292F) mutation in homozygous state. No additional mutations were found in either a 900 bp of the TPO gene promoter or PDS gene. In silico analysis showed that p.S292F mutation might reduce the catalytic cavity of the TPO which would restrict access of a potential substrate to the catalytic pocket. Using 4SNPs and one microsatellite marker in the TPO gene, an associated haplotype: G-C-G-G-214 was found, giving evidence of a founder mutation.
  
  
  CONCLUSIONS
  This is the first description of a TD causing mutation in Tunisia and thus may help to develop a genetic screening protocol for congenital hypothyroidism in the studied region. Although structural modeling suggested a pathogenic effect of this mutation, functional studies are needed. Additional causing and/or modifier genes, together with late diagnosis could explain the clinical variability observed in our patients.
authors.affiliation: Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia. noura.bougacha@gmail.com.
authors.forename: Noura
authors.initials: N
authors.lastname: Bougacha-Elleuch
authors.affiliation: Service d'Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Charfi
authors.affiliation: Laboratoire de Biochimie et de Génie Enzymatique des Lipases, Ecole Nationale d'Ingénieurs de Sfax, Route Soukra BP W, Sfax, Tunisia.
authors.forename: Nabil
authors.initials: N
authors.lastname: Miled
authors.affiliation: Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia.
authors.forename: Houda
authors.initials: H
authors.lastname: Bouhajja
authors.affiliation: Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine, Sfax, Tunisia.
authors.forename: Neila
authors.initials: N
authors.lastname: Belguith
authors.affiliation: Service d'Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia.
authors.forename: Mouna
authors.initials: M
authors.lastname: Mnif
authors.affiliation: Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal.|Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal.
authors.forename: Paula
authors.initials: P
authors.lastname: Jaurge
authors.affiliation: Service d'Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia.
authors.forename: Nessrine
authors.initials: N
authors.lastname: Chikhrouhou
authors.affiliation: Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia.
authors.forename: Hammadi
authors.initials: H
authors.lastname: Ayadi
authors.affiliation: Service de Pédiatrie, CHU Hédi Chaker, Sfax, Tunisia.
authors.forename: Mongia
authors.initials: M
authors.lastname: Hachicha
authors.affiliation: Service d'Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia.
authors.forename: Mohamed
authors.initials: M
authors.lastname: Abid
mesh_terms: D000293:Adolescent; D000328:Adult; D001324:Autoantigens / Q000235:genetics*; D002648:Child; D003409:Congenital Hypothyroidism / Q000235:genetics*; D003241:Consanguinity; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006801:Humans; D007453:Iodide Peroxidase / Q000235:genetics*; D033862:Iron-Binding Proteins / Q000235:genetics*; D008297:Male; D026901:Membrane Transport Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D010375:Pedigree; D000076988:Sulfate Transporters; D013961:Thyroid Gland / Q000002:abnormalities; D014416:Tunisia; D055815:Young Adult
chemical_list: D001324:Autoantigens; D033862:Iron-Binding Proteins; D026901:Membrane Transport Proteins; C085609:SLC26A4 protein, human; D000076988:Sulfate Transporters; C056658:TPO protein, human; D007453:Iodide Peroxidase
keywords: Founder effect; Mutation; Structural modeling; TPO; Thyroid dyshormonogenesis