Clinical and Molecular Characterization of a Novel Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Mutation (R128X)

Caterina Di Cosmo, Neil McLellan, Xiao-Hui Liao, Kum Kum Khanna, Roy E. Weiss, Laura Papp and Samuel Refetoff (2009) Clinical and Molecular Characterization of a Novel Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Mutation (R128X). Journal of Clinical Endocrinology and Metabolism, 94 10: 4003-4009. doi:10.1210/jc.2009-0686


Author Caterina Di Cosmo
Neil McLellan
Xiao-Hui Liao
Kum Kum Khanna
Roy E. Weiss
Laura Papp
Samuel Refetoff
Title Clinical and Molecular Characterization of a Novel Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Mutation (R128X)
Formatted title
Clinical and Molecular Characterization of a Novel Selenocysteine Insertion Sequence-Binding Protein 2 (SBP2) Gene Mutation (R128X)
Journal name Journal of Clinical Endocrinology and Metabolism   Check publisher's open access policy
ISSN 0021-972X
Publication date 2009-10
Year available 2009
Sub-type Article (original research)
DOI 10.1210/jc.2009-0686
Volume 94
Issue 10
Start page 4003
End page 4009
Total pages 7
Editor Leonard Wartofsky
Scott Herman
Place of publication United States
Publisher The Endocrine Society
Collection year 2010
Language eng
Subject C1
970106 Expanding Knowledge in the Biological Sciences
0601 Biochemistry and Cell Biology
Abstract Context: Although acquired abnormalities of thyroid hormone metabolism are common, inherited defects in humans involving the synthesis of selenoproteins, including iodothyronine deiodinases, have been described in only one recent publication. Objective: We report the study of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X) and its clinical and molecular characterization. Subjects and Methods: A family of African origin was studied. The proband presented with growth retardation, low serum selenium level, and thyroid test abnormalities consisting of high serum total and free T4 concentrations associated with low T3, high rT3, and normal TSH. The entire coding region of the SBP2 gene was sequenced and minigenes constructed to explain the nature of the defect. Results: The proband was homozygous for a nonsense gene mutation that produces an early stop codon (R128X). Both parents and a sister were heterozygous but showed no growth or thyroid test abnormalities. Despite the severity of the defect, the patient had a relatively mild phenotype, similar to that associated with partial SBP2 deficiency. In vitro analysis showed that the mutant minigene synthesized SBP2 from at least three downstream ATGs capable of generating molecules containing the essential functional domains. Treatment with L-T3 accelerated the growth velocity and advanced the bone age. Conclusions: We identified a novel SBP2 gene mutation producing an early arrest in the synthesis of a full-length molecule. The demonstration that SBP2 isoforms containing all functional domains could be synthesized from three downstream ATGs explains the relatively mild phenotype caused by this defect.
Formatted abstract
Context: Although acquired abnormalities of thyroid hormone metabolism are common, inherited defects in humans involving the synthesis of selenoproteins, including iodothyronine deiodinases, have been described in only one recent publication.

Objective: We report the study of a novel selenocysteine insertion sequence-binding protein 2 (SBP2) gene mutation (R128X) and its clinical and molecular characterization.

Subjects and Methods: A family of African origin was studied. The proband presented with growth retardation, low serum selenium level, and thyroid test abnormalities consisting of high serum total and free T4 concentrations associated with low T3, high rT3, and normal TSH. The entire coding region of the SBP2 gene was sequenced and minigenes constructed to explain the nature of the defect.

Results: The proband was homozygous for a nonsense gene mutation that produces an early stop codon (R128X). Both parents and a sister were heterozygous but showed no growth or thyroid test abnormalities. Despite the severity of the defect, the patient had a relatively mild phenotype, similar to that associated with partial SBP2 deficiency. In vitro analysis showed that the mutant minigene synthesized SBP2 from at least three downstream ATGs capable of generating molecules containing the essential functional domains. Treatment with L-T3 accelerated the growth velocity and advanced the bone age.

Conclusions: We identified a novel SBP2 gene mutation producing an early arrest in the synthesis of a full-length molecule. The demonstration that SBP2 isoforms containing all functional domains could be synthesized from three downstream ATGs explains the relatively mild phenotype caused by this defect.

Q-Index Code C1
Q-Index Status Provisional Code

Document type: Journal Article
Sub-type: Article (original research)
Collection: School of Medicine Publications
 
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Created: Tue, 30 Mar 2010, 15:22:26 EST by Amanda Jones on behalf of Medicine - Royal Brisbane and Women's Hospital