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Segregation of S292F TPO gene mutation in three large Tunisian families with thyroid dyshormonogenesis: evidence of a founder effect

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An Erratum to this article was published on 14 November 2015

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.

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.

What is known:

• TPO mutations are the most frequent in congenital hypothyroidism (CH) with the most severe being in the catalytic domain.

• The TPO c.875 C>T(S292F) mutation described in CH leads to hearing and intellectual impairment.

What is new:

• This is the first clinical and genetic study of CH in Tunisia with a founder c.875 C>T mutation.

• Structural modeling suggests pathogenic effects of S292F and A257S on TPO activity.

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Abbreviations

Ala:

Alanine

Arg:

Arginine

CH:

Congenital hypothyroidism

DEHAL1:

Iodotyrosine deiodinase

DNA:

Desoxyribonucleotide acid

DUOX2:

Dual oxidase 2

DUOXA2:

Dual oxidase maturation factor 2

ELISA:

Enzyme linked immunosorbent assay

FT4:

Free thyroxine

Glu:

Glutamic acid

His:

Histidine

MNG:

Multinodular goiter

NIS:

Sodium iodide symporter

PBL:

Peripheral blood lymphocyte

PCR-RFLP:

Polymerase chain reaction–restriction fragment length polymorphism

PDS:

Pendrin

Phe:

Phenylalanine

Ser:

Serine

TD:

Thyroid dyshormonogenesis

TG:

Thyroglobulin

TPO:

Thyroid peroxidase

TSH:

Thyroid stimulating hormone

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Acknowledgments

We are indebted to studied families’ members for their invaluable cooperation. This work was supported by Tunisian Ministry of High Education, Scientific Research and Technology, the Tunisian Ministry of Youth, Sports, Women and Family and the award “Loreal Unesco Pan Arab For Women in Science” 2012. We thank Mr Ryadh Koubaa, Pr. Faiza Fakhfakh, and Pr. Mounira Hmani for their critical reading of this paper.

Conflict of Interests

The authors declare that there is no conflict of interests regarding the publication of this paper.

Authors’ contributions

Genetic and Mutational analysis:

Noura Bougacha-Elleuch, Houda Bouhajja, Paula Jorge and Hammadi Ayadi.

Clinical study:

Nadia Sellami, Neila Belguith, Mouna Mnif, Nessrine Chikhrouhou, Mongia Hachicha and Mohamed Abid.

Structural Modeling:

Nabil Miled.

Author information

Authors and Affiliations

  1. Unité Cibles pour le Diagnostic et la Thérapie, Centre de Biotechnologie Sfax, BP 1177, 3018, Sfax, Tunisia

    Noura Bougacha-Elleuch, Houda Bouhajja & Hammadi Ayadi

  2. Service d’Endocrinologie, CHU Hédi Chaker, Sfax, Tunisia

    Nadia Charfi, Mouna Mnif, Nessrine Chikhrouhou & Mohamed Abid

  3. Laboratoire de Biochimie et de Génie Enzymatique des Lipases, Ecole Nationale d’Ingénieurs de Sfax, Route Soukra BP W, Sfax, Tunisia

    Nabil Miled

  4. Laboratoire de Génétique Moléculaire Humaine, Faculté de Médecine, Sfax, Tunisia

    Neila Belguith

  5. Unidade de Genética Molecular, Centro de Genética Médica Doutor Jacinto Magalhães, Centro Hospitalar do Porto, Porto, Portugal

    Paula Jaurge

  6. Unit for Multidisciplinary Research in Biomedicine, UMIB, ICBAS-UP, Porto, Portugal

    Paula Jaurge

  7. Service de Pédiatrie, CHU Hédi Chaker, Sfax, Tunisia

    Mongia Hachicha

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  1. Noura Bougacha-Elleuch
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Corresponding author

Correspondence to Noura Bougacha-Elleuch.

Additional information

Communicated by Beat Steinmann

The UMIB was funded by National Funds through FCT–Foundation for Science and Technology under the PEst-OE/SAU/UI0215/2014 project.

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Bougacha-Elleuch, N., Charfi, N., Miled, N. et al. Segregation of S292F TPO gene mutation in three large Tunisian families with thyroid dyshormonogenesis: evidence of a founder effect. Eur J Pediatr 174, 1491–1501 (2015). https://doi.org/10.1007/s00431-015-2550-4

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