Clinical and Molecular Analysis in Two Families with Novel Compound Heterozygous SBP2 (SECISBP2) Mutations

Context: Selenocysteine insertion sequence binding protein 2 (SECISBP2,
SBP2) is an essential factor for selenoprotein synthesis. Individuals with
SBP2 defects have characteristic thyroid function tests (TFT)
abnormalities due to deficiencies in the selenoenzymes deiodinases. Eight
families with recessive SBP2 gene mutations have been reported to date. We
report two families with inherited defect in thyroid hormone metabolism
caused by four novel compound heterozygous mutations in the SBP2 gene.
Case Descriptions: Proband 1 and 2 presented with growth and developmental
delay. Both had characteristic TFT with high T4, low T3, high reverse T3
and normal or slightly elevated TSH. The coding region of the SBP2 gene
was sequenced and analysis of in-vitro translated wild type and mutant
SBP2 proteins was performed. Sequencing of the SBP2 gene identified novel
compound heterozygous mutations resulting in mutant SBP2 proteins E679D
and R197* in proband 1, and K682Tfs*2 and Q782* in proband 2. In-vitro
translation of the missense E679D demonstrated all four isoforms, while
R197* had only two shorter isoforms translated from downstream ATGs, and
Q782*, K682Tfs*2 expressed isoforms with truncated C-terminus. Reduction
in serum glutathione peroxidase enzymatic activity was also demonstrated
in both probands. Conclusions: We report two additional families with
mutations in the SBP2 gene, a rare inherited condition manifesting global
selenoprotein deficiencies. Report of additional families with SBP2
deficiency and their evaluation over time is needed to determine the full
spectrum of clinical manifestations in SBP2 deficiency and increase our
understanding of the role played by SBP2 and selenoproteins in health and
disease.