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PMID:15356023

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Citation

Meeus, L, Gilbert, B, Rydlewski, C, Parma, J, Roussie, AL, Abramowicz, M, Vilain, C, Christophe, D, Costagliola, S and Vassart, G (2004) Characterization of a novel loss of function mutation of PAX8 in a familial case of congenital hypothyroidism with in-place, normal-sized thyroid. J. Clin. Endocrinol. Metab. 89:4285-91

Abstract

Thyroid dysgenesis is the most common cause of congenital hypothyroidism, a relatively frequent disease affecting 1 in 3000-4000 newborns. Whereas most cases are sporadic, mutations in transcription factors implicated in thyroid development have been shown to cause a minority of cases transmitted as monogenic Mendelian diseases. PAX8 is one of these transcription factors, and so far, five mutations have been identified in its paired domain in patients with thyroid dysgenesis. We have identified a novel mutation of PAX8, in the heterozygous state, in a father and his two children both presenting with congenital hypothyroidism associated with an in-place thyroid of normal size at birth. In addition, one of the affected siblings displayed unilateral kidney agenesis. The mutation substitutes a highly conserved serine in position 54 of the DNA-binding domain of the protein (S54G mutation) by a glycine. Functional analyses of the mutant protein (PAX8-S54G) demonstrated that it is unable to bind a specific cis-element of the thyroperoxidase gene promoter in EMSAs and that it has almost completely lost the ability to act in synergy with Titf1 to transactivate transcription from the thyroglobulin promoter/enhancer. These results indicate that loss of function mutations of the PAX8 gene may cause congenital hypothyroidism in the absence of thyroid hypoplasia.

Links

PubMed Online version:10.1210/jc.2004-0166

Keywords

Amino Acid Sequence; Base Sequence; Child; Child, Preschool; Congenital Hypothyroidism; DNA-Binding Proteins/genetics; Female; Humans; Hypothyroidism/genetics; Hypothyroidism/pathology; Male; Molecular Sequence Data; Mutation; Nuclear Proteins; Paired Box Transcription Factors; Thyroid Gland/pathology; Trans-Activators/genetics

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:PAX8

enables

GO:0000976: transcription regulatory region sequence-specific DNA binding

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:PAX8

involved_in

GO:2000612: regulation of thyroid-stimulating hormone secretion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAX8

involved_in

GO:2000611: positive regulation of thyroid hormone generation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:PAX8

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:NKX21

involved_in

GO:0045893: positive regulation of transcription, DNA-templated

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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