Cystic fibrosis. In search of the gene.
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Cystic Fibrosis↗
Biomedical subjects
V van Heyningen
Publications and source records attributed to V van Heyningen.
Tissue localization and chromosomal assignment of a serum protein that tracks the cystic fibrosis gene.
The basic gene defect in the autosomal recessive disorder cystic fibrosis has not been identified, and no firm linkage of the disorder to any other marker has been reported. However, a serum protein abnormality present in unaffected heterozygotes as well as in affected homozygotes has been described, and immunological quantitation of this protein, termed cystic fibrosis antigen, allows the three genotypes to be distinguished. We show here that an immunologically indistinguishable protein is present at high concentrations in granulocytes from normal and cystic fibrosis individuals as well as in myeloid leukaemia cells. Somatic cell hybrids between the mouse myeloid stem-cell line WEHI-TG and myeloid leukaemia cells express cystic fibrosis antigen only when human chromosome I is present.
Blood Proteins↗
The facts on cystic fibrosis testing.
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Cystic Fibrosis↗
Error rates in prenatal cystic fibrosis diagnosis.
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Cystic Fibrosis↗
A clue to the basic defect in cystic fibrosis from cloning the CF antigen gene.
The metabolic basis of the autosomal recessive disease cystic fibrosis (CF) remains unidentified. Elevated levels of a serum protein in CF homozygotes and obligate heterozygotes have been described. As heterozygotes are clinically unaffected, any consistently observed abnormality in these individuals is a likely pointer to the aetiology of the disease. The gene for this serum protein, called cystic fibrosis (CF) antigen, has been mapped to chromosome 1. It is not the gene that is mutant in CF because this has since been assigned to chromosome 7 by cosegregation of the disease with closely linked DNA markers in CF families. CF antigen is a product of normal and leukaemic granulocytes and is inducible in the promyelocytic cell line HL60 (M.N., J.D., C. Hayward, F. Northrop, D.J.H.B., J. Walker, V. van H. and D.S.S., manuscript in preparation). We have isolated cDNA clones for this protein from a library constructed with messenger RNA from chronic myeloid leukaemia (CML) cells. The complete nucleotide sequence was obtained from the cDNA clone and by primer extension of mRNA. We have confirmed that the gene encoding CF antigen is on chromosome 1 and have localized it to a particular region. RNA blot analysis shows a 550-bp major transcript in CML cells and in induced HL60. The amino-acid sequence predicted from the nucleotide sequence shows significant homology with intestinal and brain calcium-binding proteins. Abnormal accumulation of such a protein in CF is a clue which must be pursued now that evidence is gathering that the basic defect in CF is in pathways controlling chloride channel activity.
Amino Acid Sequence↗
Mouse small eye results from mutations in a paired-like homeobox-containing gene.
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.
Alleles↗
Embryonic kidney rudiments grown in adult mice fail to mimic the Wilms' phenotype, but show strain-specific morphogenesis.
12.5- to 14.5-day mouse embryonic kidney fragments were grown syngeneically under kidney or testis capsules in 3 mouse strains for 5-26 weeks to reproduce the Wilms' tumour (WT) phenotype previously reported. About 65% of the transplants grew, but none showed true WT morphology, invaded local tissue or developed metastases. In Swiss mice, most growths contained disorganized stromal and blast cells, but also had more mature structures. CBA growths had cysts, differentiated nephrons and glomeruli, while 129/SV growths gave both types of morphology. In situ mRNA hybridization using the Wilms' tumour predisposition gene (WT1) showed that, unlike the initial rudiments and WT, expression was limited to the glomeruli. The unexpected absence of expression by the apparent blast cells in the growths implies that the system is not a model for WT.
Animals↗