P.J. Scambler

Patterns of polymorphism and linkage disequilibrium for cystic fibrosis.

Four polymorphic markers that map within 80 kb of an HTF island which is genetically very close to the cystic fibrosis locus have been identified. We have analyzed the linkage disequilibrium between each of these markers and the cystic fibrosis mutation in 89 families from four European countries, Denmark, Finland, Spain, and Great Britain. Strong linkage disequilibrium between three polymorphic sites and cystic fibrosis was observed. The markers on the J3.11 (D7S8) side of the HTF island show stronger disequilibrium than those on the met side. Linkage disequilibrium between markers and disease alters the probability that a person of a given haplotype is a carrier in some populations and helps to identify regions of a sequence that are most likely to contain the cystic fibrosis mutation.

Isolation of a human gene with protein sequence similarity to human and murine int-1 and the Drosophila segment polarity mutant wingless

An expressed gene sequence which was identified by the isolation of a methylation free CpG island from human chromosome 7 has been cloned from a human lung cDNA library. The deduced protein sequence contains 360 amino acids and has several features of a secreted protein; it is cysteine rich with a signal peptide sequence and two potential asn‐linked glycosylation sites. The protein sequence shows marked similarity with human and murine int‐1 and their Drosophila homolog wingless (Dint‐1). This human int‐1 related protein, int‐1 and Dint‐1 have diverse patterns of expression, but the inferred structural similarities suggest that some of the functional characteristics of these proteins may be shared.

Routine diagnosis of DiGeorge syndrome by fluorescent in situ hybridization

In a series of ten patients affected by DiGeorge syndrome, we screened, by high resolution banding and fluorescent in situ hybridization of a cosmid probe, for microdeletions associated with this syndrome. In the ten patients, a microdeletion was demonstrated by in situ hybridization, but suspected only in two patients by high resolution banding.

Localization of 27 DNA markers to the region of human chromosome 22q11-pter deleted in patients with the DiGeorge syndrome and duplicated in the der22 syndrome.

DiGeorge syndrome is a human developmental field defect with the pathological features of an abnormality of embryogenesis at 4 to 6 weeks of gestation. Cytogenetic analyses of patients have revealed a number of instances of monosomy 22q11-pter in this condition. We have analyzed 52 DNA markers that map to 22q11-pter and have found 27 that are deleted in DiGeorge syndrome patients with known monosomy for part of this region and that are duplicated in patients with the der22 syndrome. The set of clones mapping to the DiGeorge region was further assigned to a proximal or a distal location within the deletion.

Linkage relationships of the gene for apolipoprotein CII with loci on chromosome 19

SummaryTwo common restriction fragment length polymorphisms detected with cloned gene probes for apolipoprotein CII (apo CII) have been used to study the inheritance of the gene in families segregating for loci on chromosome 19. Lod scores for APOC2 with the gene for complement component 3 (C3) exclude close linkage and give a maximum at a male recombination fraction of 0.25–0.30. Lod scores for APOC2 and FHC, the gene causing familial hypercholesterolaemia, are negative in males and suggest the genes may not be linked. However, it appears that APOC2 may be closely linked to the blood group loci Lutheran (Lu) and Secretor (Se), and probably less closely linked to Lewis (Le). These data are consistent with the gene order:

Biochemical and genetic exclusion of calmodulin as the site of the basic defect in cystic fibrosis

FHC{\text{------}}C3{\text{------}}\left( {Lu,Se,APOC2} \right)

A NEW POLYMORPHIC LOCUS, D7S411, ISOLATED BY CLONING FROM PREPARATIVE PULSE-FIELD GELS IS CLOSE TO THE MUTATION CAUSING CYSTIC-FIBROSIS

The gene coding for coagulation factor X was studied in a family segregating chromosomal abnormalities involving chromosomes 13 and 6. An individual monosomic for 13q34 was deficient in levels of clotting factors VII and X, while her brother, who is trisomic for 13q34, had elevated levels. DNA dosage studies with a cloned human factor X gene demonstrated that the low levels of factor X expression in the individual with the chromosome 13q34 deletion were due to the absence of one copy of the factor X structural gene. This confirms the assignment of the human gene coding for factor X to 13q34.