Abnormalities of the Pituitary-specific Transcription Factor-1 Gene and Protein
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概要
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Abnormalities of the pituitary-specific transcription factor-1 (Pit-1) gene cause combined deficiencies of growth hormone (GH), prolactin and thyrotropin (TSH) by altering Pit-1 protein in several different ways. The simplest are gene deletions that preclude expression of the protein. Nonsense mutations such as R172X that generate truncated proteins that lack POU specific and/or POU homeo domains and cannot bind to regulatory sites. Some missense mutations such as the Snell mouse W261C disable deoxyribnucleic acid (DNA) binding domains. Others have little effect on binding, but prevent transcriptional activation. The A158P mutation is recessive. It corresponds to "positive control" mutants in the lambda repressor that are unable to activate certain target genes, but retain the ability to silence other target genes. The R271W mutation distal to the POU homeo domain exerts dominant negative effects. Mutant proteins apparently participate in heterodimer formation and compete with active, wild type, homodimers. Alternative splicing of Pit-1 messenger ribonucleic acid (mRNA) introduces some interesting variations. Inclusion of parts of intron 1 in the protein may alter specificity of transcriptional activation. Exclusion of exon 4 bypasses the A158P and R172X mutations. If the protein encoded by this alternative splice form has a function in pituitary cell development, it may help explain the phenotypic variability seen with these mutations.
- 日本小児内分泌学会の論文
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