Genotyping of resistance to thyroid hormone in South American population. Identification of seven novel missense mutations in the human thyroid hormone receptor beta gene.
Thyroid Hormone Receptor beta (THRB) defects, typically transmitted as autosomal dominant traits, cause Resistance to Thyroid Hormone (RTH). We analyzed the THRB gene in thirteen South American patients with clinical evidence RTH from eleven unrelated families. Sequence analysis revealed seven novel missense mutations. Four novel mutations were identified in exon 9. The first, a c.991A>G transition which originates a substitution of asparagine by aspartic acid (p.N331D). The second nucleotide alteration consists of a guanine to cytosine transversion at position 1003 (c.1003G>C) and results in substitution of the alanine at codon 335 by proline (p.A335P). The third mutation, a c.1022T>C transition produces a change of leucine by proline (p.L341P). The fourth mutation detected in exon 9 was a c.1036C>T transition which replaces the leucine at codon 346 by phenylalanine (p.L346F). The sequencing of the exon 10 detected three novel missense mutations. The first, a c.1293A>G transition changing isoleucine 431 for methionine (p.I431M). The second, the cytosine at position 1339 was replaced by adenine (c.1339C>A) resulting in the replacement of proline by threonine (p.P447T). The third mutation detected in exon 10 was a c.1358C>T transition resulting in the substitution of proline at codon 453 by leucine (p.P453L). Finally, sequencing analysis of the THRB gene revealed three substitutions previously described (p.A268G, p.P453T and p.F459C). The p.P453T was found in two patients. In conclusion, we report thirteen patients with RTH caused by heterozygous mutations of the THRB gene. Seven of the identified mutations correspond to novel substitutions.
Rivolta
Carina M
CM
Laboratorio de Biología Molecular, Cátedra de Genética y Biología Molecular, Facultad de Farmacia y Bioquímica, Universidad de Buenos Aires, Buenos Aires, Argentina. crivolta@ffyb.uba.ar
Olcese
María C
MC
Belforte
Fiorella S
FS
Chiesa
Ana
A
Gruñeiro-Papendieck
Laura
L
Iorcansky
Sonia
S
Herzovich
Viviana
V
Cassorla
Fernando
F
Gauna
Alicia
A
Gonzalez-Sarmiento
Rogelio
R
Targovnik
Héctor M
HM
D002648:Child; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D017422:Sequence Analysis, DNA; D013020:South America; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics*
D037042:Thyroid Hormone Receptors beta