Carriers Of Mutant Allele Research Articles

Mortality rates among carriers of ataxia-telangiectasia mutant alleles.

Mutations at the ataxia-telangiectasia locus cause a distinctive autosomal recessive syndrome in homozygotes and predispose heterozygotes to cancer and ischemic heart disease. To examine mortality rates among persons carrying a mutated ataxia-telangiectasia gene. Retrospective cohort study. The United States and Canada. 405 grandparents of patients with ataxia-telangiectasia. Ages at death and risk for death (from all causes, cancer, ischemic heart disease, and other causes) among carriers and noncarriers of ataxia-telangiectasia mutations. Compared with noncarriers, carriers of a mutated ataxia-telangiectasia allele had a significantly increased risk for death at 20 through 79 years of age (relative risk, 1.9 [95% CI, 1.3 to 2.8]) (P < 0.001). On average, carriers died 7 to 8 years earlier than noncarriers. Cancer caused most of the excess deaths, and ischemic heart disease caused the remainder. Among carriers, relative risk for death from cancer and ischemic heart disease before 80 years of age was 2.6 (CI, 1.4 to 4.7; P = 0.002) and 2.0 (CI, 1.0 to 4.0; P = 0.062), respectively. Compared with noncarriers, carriers who died of cancer were a mean of 4 years younger (P > 0.2) and carriers who died of ischemic heart disease were a mean of 11 years younger (P = 0.006). Carriers of mutations at the ataxia-telangiectasia locus, who make up 1.4% to 2% of the general population, have a higher mortality rate and an earlier age at death from cancer and ischemic heart disease than noncarriers.

P53 mutation with frequent novel condons but not a mutator phenotype in BRCA1- and BRCA2-associated breast tumours.

The status of p53 was investigated in breast tumours arising in germ-line carriers of mutant alleles of BRCA1 and BRCA2 and in a control series of sporadic breast tumours. p53 expression was detected in 20/26 (77%) BRCA1-, 10/22 (45%) BRCA2-associated and 25/72 (35%) grade-matched sporadic tumours. Analysis of p53 sequence revealed that the gene was mutant in 33/50 (66%) BRCA-associated tumours, whereas 7/20 (35%) sporadic grade-matched tumours contained p53 mutation (P<0.05). A number of the mutations detected in the BRCA-associated tumours have not been previously described in human cancer databases, whilst others occur extremely rarely. Analysis of additional genes, p16INK4, Ki-ras and beta-globin revealed absence or very low incidence of mutations, suggesting that the higher frequency of p53 mutation in the BRCA-associated tumours does not reflect a generalized increase in susceptibility to the acquisition of somatic mutation. Furthermore, absence of frameshift mutations in the polypurine tracts present in the coding sequence of the TGF beta type II receptor (TGF beta IIR) and Bax implies that loss of function of BRCA1 or BRCA2 does not confer a mutator phenotype such as that found in tumours with microsatellite instability (MSI). p21Waf1 was expressed in BRCA-associated tumours regardless of p53 status and, furthermore, some tumours expressing wild-type p53 did not express detectable p21Waf1. These data do not support, therefore, the simple model based on studies of BRCA-/- embryos, in which mutation of p53 in BRCA-associated tumours results in loss of p21Waf1 expression and deregulated proliferation. Rather, they imply that proliferation of such tumours will be subject to multiple mechanisms of growth regulation.

The apolipoprotein E2 (Arg145Cys) mutation causes autosomal dominant type III hyperlipoproteinemia with incomplete penetrance.

Type III hyperlipoproteinemia (type III HLP) is an atherogenic disorder of lipoprotein metabolism characterized by the accumulation of cholesterol-enriched VLDL and is usually associated with homozygosity for a normal variant of apoE, apoE2. ApoE2(Arg145Cys) is a rare variant arising from a C-->T transition at nucleotide 4031 and has been linked to type III HLP. Ten subjects from a group of 42 unrelated individuals with proven type III HLP were found to be either heterozygous or homozygous for the apoE2(Arg145Cys) mutation by DNA sequencing. The apoE4-Philadelphia (Glu13Lys, Arg145Cys) variant was subsequently excluded. None of 4 homozygotes (3 blacks and 1 of mixed ancestry) developed ischemic heart disease, but they did present with xanthomata. In contrast, 6 heterozygous subjects presented mainly with ischemic heart disease but generally lacked physical signs. Cholesterol concentrations ranged from 6.2 mmol/L to 13.3 mmol/L and triglyceride levels from 3.2 to 13.2 mmol/L. The dyslipoproteinemia in homozygous and heterozygous subjects was indistinguishable. Family investigation identified an additional 10 heterozygous mutant-allele carriers, of whom 3 had type III HLP. This unique cohort of patients indicates that the apoE2(Arg145Cys) mutation is relatively common in several population groups in our region and may be particularly prevalent in blacks. There was no clear allele dosage effect present for the development of dyslipoproteinemia or atherosclerosis. The mode of inheritance is for the first time clearly established to be autosomal dominant with incomplete penetrance.

Neuroleptic sensitivity and enzyme deficiency in two schizophrenic brothers: A case report

A method for genotyping poor metabolisers of debrisoquine is based on specific polymerase chain reaction (PCR) amplification of parts of mutant genes for hepatic cytochrome P450IID6. Analysis by restriction fragment length polymorphism allowed identification of only 25% of poor metabolisers, but when it was combined with allele-specific PCR over 95% of poor metabolisers could be identified. The PCR method also allowed the identification of heterozygous carriers of mutant alleles.

HLA as a risk factor for neuroleptic induced parkinsonism in schizophrenia

A method for genotyping poor metabolisers of debrisoquine is based on specific polymerase chain reaction (PCR) amplification of parts of mutant genes for hepatic cytochrome P450IID6. Analysis by restriction fragment length polymorphism allowed identification of only 25% of poor metabolisers, but when it was combined with allele-specific PCR over 95% of poor metabolisers could be identified. The PCR method also allowed the identification of heterozygous carriers of mutant alleles.

Genotyping of poor metabolisers of debrisoquine by allele-specific PCR amplification

A method for genotyping poor metabolisers of debrisoquine is based on specific polymerase chain reaction (PCR) amplification of parts of mutant genes for hepatic cytochrome P450IID6. Analysis by restriction fragment length polymorphism allowed identification of only 25% of poor metabolisers, but when it was combined with allele-specific PCR over 95% of poor metabolisers could be identified. The PCR method also allowed the identification of heterozygous carriers of mutant alleles.

A closely linked genetic marker for cystic fibrosis.

Cystic fibrosis is a recessive genetic disorder, characterized clinically by chronic obstructive lung disease, pancreatic insufficiency and elevated sweat electrolytes; affected individuals rarely live past their early twenties. Cystic fibrosis is also one of the most common genetic diseases in the northern European population. The frequency of carriers of mutant alleles in some populations is estimated to be as high as 1 in 20, carrying a concomitant burden of about one affected child in 1,500 births. Because little is known of the essential biochemical defect caused by the mutant gene, a genetic linkage approach based on arbitrary genetic markers and family studies is indicated to determine the chromosomal location of the cystic fibrosis (CF) gene. We have now obtained evidence for tight linkage between the CF locus and a DNA sequence polymorphism at the met oncogene locus. This evidence, combined with the physical localization data for the met locus presented in the accompanying paper, places the CF locus in the middle third of the long arm of chromosome 7, probably between bands q21 and q31.

Modification of Radiosensitivity of Genetically Anemic Mice by Implantation of Blood-Forming Tissue

The dependence of acute radiation sensitivity on the genotypes of the functioning blood-forming tissue was demonstrated by testing the radiation reaction of WW/sup v/ anemic mice successfully implanted with isologous normal ww blood-forming tissue. The LD/sub 50(30)/ values of such mice was raised from approximately 250 r to about 680 r, a figure approaching the level of normal ww individuals. Modification of radiation sensitivity of carriers of mutant alleles of the W-series in a single dose (W/sup v/w and Ww) has also been achieved by implantation. ln each case the LD/sub 50/ value has been increased to a level characteristic of normal mice of this strain. These investigations lead to the conclusion that in the case of the W-series anemias the acute radiosensitivity of the entire organism is, in large measure, dependent on the genetic constitution of the cells residing in the marrow. (auth)