title: Pituitary dwarfism in the R271W Pit-1 gene mutation.
abstract: The Pit-1 gene encodes the POU-domain transcription factor Pit-1 which is important for the differentiation of the anterior pituitary and regulation of the PRL, GH and TSH genes. As a member of the POU domain transcription factors, Pit-1 contains a DNA-binding region, consisting of a POU-specific domain and a POU homeodomain. Mutation of the Pit-1 gene causes hypoplasia of the pituitary gland and deficiencies of GH, PRL and TSH. In a DNA sample from a 3-month-old girl with severe growth deficiency from birth, single stranded conformational polymorphism analysis of the Pit-1 gene identified a gel shift in exon 6. DNA-sequencing disclosed a single base mutation in codon 271 (CGG to TGG) that changes arginine to tryptophan (R271W) in the POU homeodomain. The patient presented distinct facial features with prominent forehead, marked mid-facial hypoplasia with depressed nasal bridge, deep-set eyes and a short nose with anteverted nostrils. MRI examination showed a hypoplastic pituitary gland. Low serum GH did not respond to insulin-arginine provocation or GHRH tests. PRL levels below the detection limit did not increase in response to a TRH test. T4 and free T4 was below detection limit (< 20 nmol/l and < 4 pmol/l). TSH was 2.0 mU/l and showed a blunt response to 6.0 mU/l following TRH test. TBG was normal. In spite of inappropriately low TSH and very low T4, T3 was in the low normal range (1.4-1.6 nmol/l) and she was clinically euthyroid. The thyroid function tests are consistent with increased monodeiodination activity and increased conversion of T4 to T3, possibly related to the Pit-1 gene mutation. GH and T4 treatment resulted in catch-up growth continued during 5 years of therapy.
  
  
  CONCLUSIONS
  Reports of nine other cases of R271W mutations of different populations as well as the present Norwegian patient suggest codon 271 of exon 6 to be a "hot spot" for Pit-1 mutations. To enable rapid and simple detection of this type of de novo mutation we have designed a specific amplification-created-restriction-site assay to check for the R271W mutation in patients suspected to have this rare form of genetic defect in growth hormone production.
authors.affiliation: Barneklinikken, Bergen, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Aarskog
authors.forename: H G
authors.initials: HG
authors.lastname: Eiken
authors.forename: R
authors.initials: R
authors.lastname: Bjerknes
authors.forename: O L
authors.initials: OL
authors.lastname: Myking
mesh_terms: D001120:Arginine; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004392:Dwarfism / Q000235:genetics* / Q000378:metabolism; D005260:Female; D018398:Homeodomain Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D007223:Infant; D009154:Mutation; D010902:Pituitary Gland / Q000378:metabolism; D010907:Pituitary Hormones / Q000378:metabolism; D018807:Polymorphism, Single-Stranded Conformational; D013963:Thyroid Hormones / Q000378:metabolism; D050817:Transcription Factor Pit-1; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D014364:Tryptophan
chemical_list: D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; C494187:POU1F1 protein, human; D010907:Pituitary Hormones; D013963:Thyroid Hormones; D050817:Transcription Factor Pit-1; D014157:Transcription Factors; D014364:Tryptophan; D001120:Arginine