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M Farrall

Publications and source records attributed to M Farrall.

At least 91 records · Page 5Linked to original sources
PubMed1987

Exclusion of catalytic and regulatory subunits of cAMP-dependent protein kinase as candidate genes for the defect causing cystic fibrosis.

Cystic fibrosis (CF) is a common autosomal recessive disease with significant morbidity and mortality. Defects in cAMP control mechanisms are implicated in the pathophysiology of the disease. The mutation causing CF has been localized to chromosome 7q22-7q31.1. We have used (1) somatic-cell hybrids containing this region of the human genome in a mouse background and (2) segregation analysis in families to exclude both the genes coding for a catalytic subunit and three distinct regulatory subunits of cAMP-dependent protein kinase as candidates for the gene defect in CF. Two of these genes--those for the human homologue of the mouse type I regulatory subunit and the human homologue of the rat type II regulatory subunit--map to human chromosome 7.

Animals↗
PubMed1986

Genetic homogeneity of cystic fibrosis.

We studied large Amish/Mennonite/Hutterite kindreds that segregate cystic fibrosis (CF) for linkage between CF and the polymorphic DNA markers pJ3.11 and 7C22 located on chromosome 7. These inbred pedigrees consist of more than 300 members including 30 affected individuals. In these families, linkage between the CF locus and the chromosome 21 marker D21S5 and between CF and the marker at the met oncogene locus on chromosome 7 had been previously indicated. We now report linkage between CF and pJ3.11 (Z = 4.92, theta = 0) and between CF and 7C22 (Z = 3.42, theta = 0). Therefore, CF segregates in these large pedigrees in a manner consistent with data from smaller outbred families with respect to the markers on chromosome 7 closest to CF. These data are consistent with locus homogeneity for the defect causing CF in the populations that have been examined to date.

Chromosomes, Human, Pair 21↗
PubMed1986

First-trimester prenatal diagnosis of cystic fibrosis with linked DNA probes.

Linkage analysis with cloned gene probes has shown that the mutation causing cystic fibrosis is located in the middle of the long arm of chromosome 7. First-trimester diagnosis of cystic fibrosis is reported in four informative families and second-trimester diagnosis in one family with fetal DNA prepared from chorionic villi, hybridised with the tightly linked DNA probes, pJ3.11 and met. Risk calculations show that the expected false-negative and false-positive rates are approximately 2% and 6%, respectively, for typical nuclear families with one affected living child. Existing probes are sufficiently informative to allow full diagnosis in about two-thirds of couples presenting with at least one affected child. In half of the remainder, the inheritance of one parental mutant chromosome can be deduced.

Biopsy↗
PubMed1986

Isolation of a further anonymous informative DNA sequence from chromosome seven closely linked to cystic fibrosis.

A library prepared from flow-sorted chromosomes was used to isolate single-copy sequences from chromosome seven. One such sequence 7C22 has been shown to be polymorphic for an EcoRI restriction site and to be informative for the study of CF in approximately 35% of matings. The segregation of the 7C22 alleles was followed through nineteen informative families with more than one child affected by cystic fibrosis. We report that the locus for 7C22 is linked to the locus for cystic fibrosis at a recombination fraction of 0.045. This marker will prove useful in improving the accuracy and informativeness of prenatal diagnosis and in constructing a fine genetic map around the cystic fibrosis gene.

Chromosomes, Human, 6-12 and X↗
PubMed1986

Cystic fibrosis carrier detection using a linked gene probe.

Cloned DNA markers which are closely linked to the gene defect causing cystic fibrosis have recently been described. These markers are sufficiently informative for carrier detection in 80% of families where there is a living cystic fibrosis child and unaffected sibs. The tightly linked DNA marker pJ3.11 was used in this study to identify carriers in six families and exclude carrier status in two subjects. Risk calculations for recessive diseases using linked DNA probes may be complex, but useful information for counselling can be obtained in this way.

Cloning, Molecular↗
PubMed1986

A model system for the analysis of gene exclusion: cystic fibrosis and chromosome 19.

We have used multilocus analysis to exclude the cystic fibrosis locus from six polymorphic DNA markers covering most of chromosome 19. A substantial increase in the confidence for exclusion was obtained using the computer programme LINKAGE compared to analysis of pairwise lod scores. A structured approach to the analysis of linkage to autosomal recessive inherited diseases where the biochemical defect is not known is described.

Child↗
PubMed1986

The analysis of multiple polymorphic loci on a single human chromosome to exclude linkage to inherited disease: cystic fibrosis and chromosome 4.

Classical linkage programs analyze the segregation of two markers in informative families. When several markers are available for one human chromosome, pairwise analysis can exclude linkage between each marker and an inherited disease. The identification of restriction fragment length polymorphisms has made many new informative markers, assigned to chromosomes, available. We have adapted the multipoint linkage program MLINK developed by Lathrop et al. in order to exclude linkage between cystic fibrosis and several markers known to be on human chromosome 4. The exclusion obtained is greater than that for a pairwise analysis.

Chromosome Mapping↗
PubMed1986

Linkage of cystic fibrosis to two tightly linked DNA markers: joint report from a collaborative study.

A collaborative study involving seven research groups provided an opportunity to investigate the linkage relationships between cystic fibrosis and two DNA marker loci, MET and pJ3.11 (D7S8), on an extended sample of 211 tested families. The maximum lod scores, recombination estimates, and confidence upper bounds (in parentheses) were 91.0 at theta = .004 (.012) for CF and MET, 71.3 at theta = .003 (.011) for CF and D7S8, and 69.3 at theta = .018 (.036) for MET and D7S8. Three-locus analyses yielded best support for the order MET-CF-D7S8, with odds against the alternate orders CF-MET-D7S8 and CF-D7S8-MET of 9:1 and 161:1, respectively. However, the number of observed recombinants was small and only one of the recombinants was jointly informative for all three markers. Significant allelic association was found between CF and both MET and D7S8. Weaker association between the latter two loci is consistent with the order MET-CF-D7S8.

Alleles↗
PubMed1986

Further data supporting linkage between cystic fibrosis and the met oncogene and haplotype analysis with met and pJ3.11.

The linkage of cystic fibrosis (CF) and the polymorphic DNA markers pJ3.11, met, 7C22, DOCR1-917, COL1A2, and TCRB have jointly localized the mutation causing CF to chromosome 7q2.1-3.1. We report further linkage data with two polymorphic markers at the met oncogene locus, pmetH and pmetD, which supports the tight linkage found by White et al. between CF and met. One family shows evidence for meiotic recombination between CF and met. Analysis of haplotypes in CF pedigrees collected for linkage studies combined with data from single affected families requesting prenatal diagnosis (Farrall et al., Lancet i:1402-1404, 1986) shows CF and met to be in linkage equilibrium in our population while pJ3.11-CF haplotypes show a deviation from the equilibrium frequencies.

Cystic Fibrosis↗
PubMedDate not supplied

Localization of cystic fibrosis locus to human chromosome 7cen-q22.

Cystic fibrosis (CF) is the most common genetic disease in Caucasian populations, with an incidence of 1 in 2,000 live births in the United Kingdom, and a carrier frequency of approximately 1 in 20. The biochemical basis of the disease is not known, although membrane transport phenomena associated with CF have been described recently. Consanguinity studies have shown that the inheritance of CF is consistent with it being a recessive defect caused by a mutation at a single autosomal locus. Eiberg et al. have reported a genetic linkage between the CF locus and a polymorphic locus controlling activity of the serum aryl esterase paraoxonase (PON). The chromosomal location of PON, however, is not known. Linkage to a DNA probe, DOCR1-917, was also recently found at a genetic distance of approximately 15 centimorgans (L.-C. Tsui and H. Donnis-Keller, personal communication), but no chromosomal localization was given. Here we report tight linkage between the CF locus and an anonymous DNA probe, pJ3.11, which has been assigned to chromosome 7cen-q22.

Chromosome Mapping↗
PubMedDate not supplied

Linkage of an X-chromosome cleft palate gene.

Many congenital malformations, such as cleft palate and neural tube defects, have a multifactorial origin involving both environmental and genetic factors. Conditions such as these may be exclusively monogenic, polygenic or environmental, but in most cases both genetic and environmental factors are involved. This study describes the sub-chromosomal localization of a single gene defect causing cleft palate and ankyloglossia (tongue-tied) in a large Icelandic family. This defect is a model for the analysis of other neural-crest malformations that show a more complex multifactorial inheritance pattern.

Cleft Palate↗
PubMedDate not supplied

A candidate for the cystic fibrosis locus isolated by selection for methylation-free islands.

A genomic sequence close to the cystic fibrosis locus with the characteristics of an HTF island has been selectively cloned and characterized. Two markers flanking this sequence, which is conserved throughout mammalian evolution, show a very much greater disequilibrium than that found with any existing marker. A single mutational event accounts for most cases of cystic fibrosis. The sequence is expressed, and is a candidate for the cystic fibrosis gene.

Animals↗