Noura Bougacha-Elleuch1, Nadia Charfi2, Nabil Miled3, Houda Bouhajja4, Neila Belguith5, Mouna Mnif2, Paula Jaurge6,7, Nessrine Chikhrouhou2, Hammadi Ayadi4, Mongia Hachicha8, Mohamed Abid2. 1. Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia. noura.bougacha@gmail.com. 2. Service d'Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia. 3. Laboratoire de Biochimie et de Génie Enzymatique des Lipases, Ecole Nationale d'Ingénieurs de Sfax, Route Soukra BP W, Sfax, Tunisia. 4. Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia. 5. Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine, Sfax, Tunisia. 6. Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal. 7. Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal. 8. Service de Pédiatrie, CHU Hédi Chaker, Sfax, Tunisia.
Abstract
UNLABELLED: 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. CONCLUSION: 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.
UNLABELLED: 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. CONCLUSION: 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: Fiorella S Belforte; Mirta B Miras; María C Olcese; Gabriela Sobrero; Graciela Testa; Liliana Muñoz; Laura Gruñeiro-Papendieck; Ana Chiesa; Rogelio González-Sarmiento; Héctor M Targovnik; Carina M Rivolta Journal: Clin Endocrinol (Oxf) Date: 2012-04 Impact factor: 3.478
Authors: José C Moreno; Willem Klootwijk; Hans van Toor; Graziella Pinto; Mariella D'Alessandro; Aubène Lèger; David Goudie; Michel Polak; Annette Grüters; Theo J Visser Journal: N Engl J Med Date: 2008-04-24 Impact factor: 91.245