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Authors
Advisor(s)
Abstract(s)
Congenital primary hypothyroidism (CH) affects about 1:3000 to 1:4000 infants and
may be caused by defects in thyroidal ontogeny or hormone synthesis. In the past two decades,
there were impressive advances in molecular genetics that lead to characterization of
numerous genes that are essential for normal development and hormone production of the
hypothalamic-pituitary-thyroid axis and for normal thyroid hormone synthesis. Mutations
identified in these genes allowed the molecular caracterization of several sporadic and
familial HC forms.
Defects in the thyroid peroxidase (TPO) gene are reported to be one of the causes of
congenital hypothyroidism (CH) due to thyroid hormone biosynthesis defect (thyroid
dyshormonogenesis). The aim of the present study was to determine the nature and frequency
of TPO gene mutations in patients with CH, characterized by elevated thyroid stimulating
hormone (TSH) levels and orthopic thyroid gland, identified in the Portuguese National
Neonatal Screening Programme.
The sample comprised 55 patients, from 52 unrelated families, with follow-up in the
endocrinology clinics of the treatment centres of Porto and Lisbon. Mutation screening in the
TPO gene (exons 1-17) was performed by single-strand conformational analysis (SSCA)
followed by sequencing of fragments with abnormal migration patterns.
Eight different mutations were detected in 13 patients (7 homozygotes, 6 compound
heterozygotes). Novel mutations included 3 missense mutations namely c.391T>C (p.S131P),
c.1274A>G (p.N425S), c.2512T>A (p.C838S) as well as the predictable splice mutation
c.2748G>A. The undocumented polymorphism c.180-47A>C, was also detected.
The two most frequent mutations were c.1978C>G (p.Q660E) and
c.1183_1186dupGGCC (p.R396fsX76). In order to establish the genetic background
associated to these two most frequent mutations, haplotype analysis was done in patients and
relatives using intragenic markers. The results suggested a common origin for each of these
mutations.
This is the first molecular study ever performed in Portuguese CH patients to establish
the aetiology of CH due to a hormonogenic defect. The large proportion of patients found to
have TPO mutations (approximately 24% of our sample) justifies the implementation of
routine molecular testing.
Description
Keywords
Rastreio genético
Citation
Rodrigues, Carina (2004). Rastreio molecular do gene da peroxidase da tiróide em doentes com hipotiroidismo congénito. Braga: Universidade do Minho. Tese de Mestrado em Genética Molecular.