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Abstract

Cretinism is marked by irreversible mental and growth retardation. We describe here an entirely new case of cretinism showing combined pituitary hormone deficiencies of thyrotropin, growth hormone and prolactin that appears to be caused by homozygosity for a nonsense mutation in the gene for the pituitary specific transcription activator, Pit-1/GHF-1 (designated PIT1 in humans for pituitary specific factor 1). This is the first report in humans of a defect in a transcription activator causing deficiency of multiple target genes.

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Mouse small eye results from mutations in a paired-like homeobox-containing gene.

R Hill, J Favor, B Hogan … (1991)

Small eye (Sey) in mouse is a semidominant mutation which in the homozygous condition results in the complete lack of eyes and nasal primordia. On the basis of comparative mapping studies and on phenotypic similarities, Sey has been suggested to be homologous to congenital aniridia (lack of iris) in human. A candidate gene for the aniridia (AN) locus at 11p13 has been isolated by positional cloning and its sequence and that of the mouse homologue has been established (C.T., manuscript in preparation). This gene belongs to the paired-like class of developmental genes first described in Drosophila which contain two highly conserved motifs, the paired box and the homeobox. In vertebrates, genes which encode the single paired domain as well as those which express both motifs have been described as the Pax multigene family. A Pax gene recently described as Pax-6 is identical to the mouse homologue of the candidate aniridia gene. Here we report the analysis of three independent Sey alleles and show that indeed this gene is mutated and that the mutations would predictably interrupt gene function.

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Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1.

Charles E. Robertson, F. COSTANTINI, S Orkin … (1991)

The zinc-finger transcription factor GATA-1 (previously known as GF-1, NF-E1 or Eryf 1 binds to GATA consensus elements in regulatory regions of the alpha- and beta-globin gene clusters and other erythroid cell-specific genes. Analysis of the effects of mutations in GATA-binding sites in cell culture and in binding assays in vitro, as well as transactivation studies with GATA-1 expression vectors in heterologous cells, have provided indirect evidence that this factor is involved in the activation of globin and other genes during erythroid cell maturation. GATA-1 is also expressed in megakaryocytes and mast cells, but not in other blood cell lineages or in non-haemopoietic cells. To investigate the role of this factor in haematopoiesis in vivo, we disrupted the X-linked GATA-1 gene by homologous recombination in a male (XY) murine embryonic stem cell line and tested the GATA-1-deficient cells for their ability to contribute to different tissues in chimaeric mice. The mutant embryonic stem cells contributed to all non-haemopoietic tissues tested and to a white blood cell fraction, but failed to give rise to mature red blood cells. This demonstrates that GATA-1 is required for the normal differentiation of erythroid cells, and that other GATA-binding proteins cannot compensate for its absence.

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A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.

M Mucenski, K McLain, A Kier … (1991)

The c-myb proto-oncogene encodes a sequence-specific DNA-binding protein. To better understand its normal biological function, we have altered the c-myb gene by homologous recombination in mouse embryonic stem cells. Resulting homozygous c-myb mutant mice displayed an interesting phenotype. At day 13 of gestation these mice appeared normal, suggesting that c-myb is not essential for early development. By day 15, however, the mutant mice were severely anemic. Analysis indicated that embryonic erythropoiesis, which occurs in the yolk sac, was not impaired by the c-myb alteration. Adult-type erythropoiesis, which first takes place in the fetal liver, was greatly diminished in c-myb mutants, however. Additional hematopoietic lineages were similarly affected. These results are compatible with a role for c-myb in maintaining the proliferative state of hematopoietic progenitor cells.

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PubMed ID:: 1302000

DOI:: 10.1038/ng0492-56

ScienceOpen disciplines: Chemistry

Keywords: Amino Acid Sequence,Base Sequence,Congenital Hypothyroidism,genetics,metabolism,Consanguinity,DNA,DNA-Binding Proteins,Female,Growth Hormone,deficiency,Hormones,Humans,Male,Molecular Sequence Data,Pedigree,Point Mutation,Prolactin,Thyrotropin,Transcription Factor Pit-1,Transcription Factors

Cretinism with combined hormone deficiency caused by a mutation in the PIT1 gene.

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Most cited references 35

Mouse small eye results from mutations in a paired-like homeobox-containing gene.

Erythroid differentiation in chimaeric mice blocked by a targeted mutation in the gene for transcription factor GATA-1.

A functional c-myb gene is required for normal murine fetal hepatic hematopoiesis.

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