Mutations in SECISBP2 result in abnormal thyroid hormone metabolism

Area of Science:

• Biochemistry
• Genetics
• Endocrinology

Background:

• Selenocysteine (Sec) incorporation, via UGA codon recoding, generates unique selenoproteins.
• While tRNA(Sec) deficiency is lethal in mice, the in vivo roles of other selenoprotein synthesis factors and human Sec incorporation defects remain largely unknown.
• Deiodinases (DIOs), crucial for thyroid hormone metabolism, are selenoproteins.

Purpose of the Study:

• To investigate the genetic basis of inherited defects in selenoprotein synthesis and their impact on thyroid hormone metabolism in humans.
• To identify the specific gene and mutations responsible for Sec incorporation defects leading to abnormal thyroid hormone activity.

Main Methods:

• Clinical evaluation of siblings with suspected thyroid hormone metabolism abnormalities.
• Fibroblast analysis to assess DIO2 enzymatic activity.
• Systematic linkage analysis of genes involved in DIO2 synthesis and degradation, focusing on SECISBP2.

Main Results:

• Identified three siblings with clinical signs of abnormal thyroid hormone metabolism and decreased DIO2 activity in fibroblasts.
• Discovered an inherited Sec incorporation defect in SECISBP2 (SBP2) due to a homozygous missense mutation in affected siblings.
• An unrelated child with a similar phenotype was found to be compound heterozygous for SECISBP2 mutations.
• Demonstrated that SBP2 defects have a generalized impact on selenoproteins due to its epistatic role in selenoprotein synthesis.

Conclusions:

• Inherited mutations in SECISBP2 cause Sec incorporation defects, leading to abnormal thyroid hormone metabolism.
• The identified SECISBP2 mutations result in a generalized defect in selenoprotein synthesis.
• Incomplete loss of SBP2 function likely explains the observed mild clinical phenotype.