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Horm Metab Res 2012; 44(09): 704-707
DOI: 10.1055/s-0032-1312666
Short Communication
© Georg Thieme Verlag KG Stuttgart · New York

A Novel p.E311K Mutation of Thyroid Receptor Beta Gene in Resistance to Thyroid Hormone Syndrome, Inherited in Autosomal Recessive Trait

R. Slezak
1   Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
,
T. Lukienczuk
2   First Department and Clinic of General, Gastroenterological and Endocrinological Surgery, Wroclaw Medical University, Wroclaw, Poland
,
A. Noczynska
3   Department and Clinic of Endocrinology and Diabetology for Children and Adolescents, Wroclaw Medical University, Wroclaw, Poland
,
P. Karpinski
1   Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
,
A. Lebioda
4   Department of Forensic Medicine, Wroclaw Medical University, Wroclaw, Poland
,
B. Misiak
1   Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
,
M. M. Sasiadek
1   Department of Genetics, Wroclaw Medical University, Wroclaw, Poland
› Author Affiliations
Further Information

Publication History

received 06 November 2011

accepted 23 April 2012

Publication Date:
13 June 2012 (online)

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Abstract

Resistance to thyroid hormone (RTH) syndrome is caused by mutations in THRB gene and is inherited mainly as an autosomal dominant trait with dominant negative effect. Most of up-to-now described RTH cases were heterozygous. We studied a 19-year-old woman presenting severe mental impairment, hyperkinetic behavior, learning disability, hearing loss, tachycardia, goiter, strabismus, nystagmus, and normal stature. The laboratory findings revealed elevated TSH, T3, and T4 serum levels. Her parents were healthy with normal serum level of TSH, fT3, and fT4. Sequence based prediction of a substitution was analyzed by SDM, PolPhen, and SNAP software whereas structural visualizations were performed in UCSF Chimera. We found a novel mutation in THRB gene in position 1216 (G to A transition, codon 311) resulting in novel Glu-311-Lys (p.E311K) substitution, homozygous in proband presenting with severe symptoms of RTH and heterozygous in both of her healthy parents, thus suggesting autosomal recessive mode of inheritance. p.E311K substitution was not found in 50 healthy, unrelated individuals. p.E311K was shown to be deleterious by SDM, PolPhen, and SNAP software. Structural visualizations of mutated protein performed by UCSF Chimera software disclosed a loss of hydrogen bonds between E311, R383, and R429 along with abnormal residue-residue contact between K311 and L377. This is a very rare case of a homozygous mutation in a patient with severe symptoms of RTH and lack of symptoms in both heterozygous parents. Although, computational analyses have provided the evidence that p.E311K substitution may affect THRB function, lack of dominant negative effect typical for THRB mutations could not be explained by structure-based modeling. Further in vitro analysis is required to assess the functional consequences of this substitution.