Search PubMed⌕ Search

Biomedical subjects

M H Skolnick

Publications and source records attributed to M H Skolnick.

At least 109 records · Page 6Linked to original sources
PubMed1986

An approach to monitoring mutation rates using restriction fragment lengths.

Monitoring background mutation rates in normal populations, elevated rates in exposed populations and unusual rates in test systems exposed to mutagens and carcinogens remains an unresolved problem. To date, efforts have focused on measurement of mutation rates by searching for protein sequences that appear in children but were not present in their parents. An initial study to measure mutation rates by using recombinant DNA technology was carried out in Alta, Utah, in 1984, and the results are summarized here. The purpose of this paper is to explore in greater detail the use of restriction fragment lengths for monitoring mutation rates. The report of the meeting at Alta was sceptical about the practicality of this approach. The conclusion of this paper is that it is indeed a practical approach, and details are given of a method for realizing a functional system.

DNA↗
PubMed1986

Relationships between the human pepsinogen DNA and protein polymorphisms.

Pepsinogens (PGA) are the inactive precursors of pepsin, the major acid protease found in the stomach. The PGA gene family exhibits polymorphic variation in human populations that can either be demonstrated by electrophoretic analysis of the proteins or by analysis of the respective genes with cDNA probes. Here, we describe the interrelationships between the most common pepsinogen protein phenotypes and the corresponding pepsinogen haplotypes (A, B, and C) containing different combinations of the PGA3, PGA4, and PGA5 genes. We propose that this unusual genetic variation involving haplotypes that contain three, two, and one genes, respectively, is the result of molecular evolution by gene duplication.

Chromosomes, Human, 6-12 and X↗
PubMed1986

Mapping the locus for hereditary hemochromatosis: localization between HLA-B and HLA-A.

We studied a family with HLA-linked hereditary hemochromatosis in which an informative recombination occurred within the HLA region. The father, an obligate heterozygote for hereditary hemochromatosis, had HLA haplotypes A2,B13 and A11,B27. The mother, also an obligate heterozygote, had HLA haplotypes A29,B44 and A2,B7. Three haplotypes were found among three homozygous affected offspring. Two affected siblings were HLA-identical with haplotypes A2,B13 and A29,B44. The proband had HLA haplotypes A2,B13 and A2,B44, the latter a recombinant haplotype inherited from her mother. Since the maternal hemochromatosis allele was linked to the A29,B44 haplotype, and since the proband has hemochromatosis, the maternal hemochromatosis allele was transmitted to the proband with the B44 antigen. This is the first known example of recombination in an individual with HLA-linked hemochromatosis in whom the hemochromatosis allele appeared to segregate with the HLA-B antigen instead of the -A antigen. The possibility of either a double reciprocal recombination event or a gene conversion event cannot be excluded. Combined with earlier observations of segregation of the hemochromatosis allele with the A locus in HLA recombinants, the findings in this pedigree map the hemochromatosis locus between the HLA-B and HLA-A loci rather than outside the HLA region.

Adult↗
PubMed1986

The incidence and gene frequency of ataxia-telangiectasia in the United States.

Ataxia-telangiectasia (A-T) is an autosomal recessive neurological syndrome of considerable interest because homozygotes are highly predisposed to cancer. Vigorous casefinding in the United States in 1970-72 and 1980-84 identified 231 white, 29 black, and three Oriental A-T cases that provide information about the incidence and gene frequency of A-T. White patients identified in this study were born at the rate of 3.0 per million live births in the U.S. in the years 1965-69. The highest observed incidence was in the state of Michigan for 1965-69, where identified white A-T patients were born at the rate of 11.3 per million births. Based on the incidence data, the minimum frequency of a single hypothetical A-T gene in the U.S. white population was estimated to be .0017. Pedigree analysis, which estimates the gene frequency from the proportion of affected close blood relatives of homozygous probands, estimated the most likely gene frequency to be .007 on the assumption that A-T is a single homogeneous genetic syndrome, with 95% confidence limits of .0012-.02. Given that complementation analysis has demonstrated the genetic heterogeneity of A-T, the A-T heterozygote frequency will probably fall between 0.68% and 7.7%, with 2.8% being the most likely estimate.

Ataxia Telangiectasia↗
PubMed1985

Dominant inheritance of adenomatous colonic polyps and colorectal cancer.

Except in the rare polyposis syndromes, the contribution of heritable factors to the genesis of colorectal cancer and adenomatous polyps is not well understood. We examined the inheritance of susceptibility to colonic polyps and cancer in a large Utah pedigree with multiple cases of common colorectal cancer but no recognizable inheritance pattern among them. Inheritance was clarified, however, by systematic screening for colonic polyps in pedigree members and spouse controls, using flexible proctosigmoidoscopy. One or more adenomatous polyps were found in 21 per cent of family members (41 of 191) but in only 9 per cent of controls (12 of 132) (P less than 0.005). Pedigree analysis was performed with likelihood methods that compared random occurrence of cancer and polyps with autosomal recessive and autosomal dominant patterns of inheritance. The analysis suggested that the observed excess of discrete adenomatous polyps and colorectal cancers was the result of an inherited autosomal dominant gene for susceptibility, rather than an inherited recessive gene for susceptibility or a chance occurrence. This type of inheritance of colorectal polyps and cancer may be more common than previously recognized.

Adult↗
PubMed1985

Heterozygosity for HLA-linked hemochromatosis as a likely cause of the hepatic siderosis associated with sporadic porphyria cutanea tarda.

Subnormal activity of hepatic uroporphyrinogen decarboxylase is responsible for the derangement of porphyrin biosynthesis in both sporadic and familial porphyria cutanea tarda, but the enzymatic defect is not clinically expressed in the absence of hepatic siderosis. The pedigree study described here offers support for the hypothesis that a single allele for HLA-linked hereditary hemochromatosis is responsible for the hepatic siderosis in sporadic porphyria cutanea tarda. A two-locus causation model for sporadic porphyria cutanea tarda might explain both the observed incidence of overt cases and the rarity of multiple affected individuals within a pedigree.

Adult↗
PubMed1985

Hereditary thrombosis in a Utah kindred is caused by a dysfunctional antithrombin III gene.

Maximum likelihood analysis of linkage between antithrombin III (ATIII) DNA polymorphisms and ATIII deficiency in a large Utah kindred suggests that thrombotic disease in this family is caused by a dysfunctional ATIII gene. ATIII-deficient family members were identified on the basis of: (1) reduced anticoagulant activity and (2) the presence of an electrophoretically abnormal inhibitor molecule in their plasmas. Affected individuals have two copies of the ATIII structural gene, and both alleles appear normal at the resolution of whole genome Southern blotting. However, family studies revealed statistically significant cosegregation of ATIII-deficiency trait and a particular ATIII DNA polymorphism haplotype (lod = 3.35; theta = 0.0); this result is consistent with the presence of a dysfunctional ATIII gene on a chromosome of the +, S haplotype.

Alleles↗
PubMed1984

Genetic Analysis Workshop II: segregation and three-locus linkage analysis.

Data stimulated for Genetic Analysis Workshop II were analyzed using PAP. Segregation analysis showed a simple recessive mode of inheritance for data set 2 while no conclusions could be made about the mode of inheritance for data set 3. Pairwise linkage analysis suggested three linkage groups, but three-locus analysis did not provide strong evidence for the gene order within these groups. For three of the four three-locus comparisons performed, three-locus analysis suggested the simulated order. In only one case did the pairwise analysis suggest the simulated order, indicating the necessity for multi-locus analysis for gene order.

Chromosome Mapping↗
PubMed1984

Possible linkage of a breast cancer-susceptibility locus to the ABO locus: sensitivity of LOD scores to a single new recombinant observation.

We present evidence of a pedigree in which a major gene for breast cancer-susceptibility appears to segregate in a dominant fashion. Linkage analysis suggests that the breast cancer-susceptibility locus in this family may be linked to the ABO locus, which is located on band q34 of chromosome 9. At an early stage in the analysis, a LOD score of 3.0 for zero recombination was obtained for linkage between ABO and the susceptibility locus, but a single recombinant reduced the LOD score to 1.72 at a recombination fraction of 0.06. A final observation of a nonrecombinant brings the LOD score for this pedigree to 1.99 at theta = 0.05. We attempt to put these results in perspective by discussing the sensitivity of the LOD score to the next observation. Examples of the volatility of LOD scores are given. These simple calculations show that tight linkage represents the worst case for the interpretation of a LOD score of 3.0. Finally, we discuss the linkage between the breast cancer-susceptibility locus and the ABO blood group and approaches to confirming or denying this result.

ABO Blood-Group System↗
PubMed1984

Thermostable erythrocyte rosette-forming lymphocytes in hereditary hemochromatosis. I. Identification in peripheral blood.

Although the immunoregulatory role of iron has been demonstrated in vitro, evidence for a similar role in vivo is controversial. We have, therefore, studied certain functional and structural properties of lymphocytes in hereditary (idiopathic) hemochromatosis (HH), a disease characterized by iron overload. T- and B-lymphocyte percentages in peripheral blood, serum immunoglobulin levels, and proliferative responses of peripheral blood mononuclear cells (PBM) to lectins were comparable with those of controls. Furthermore, HH serum with elevated iron concentrations did not significantly alter proliferative responses of normal lymphocytes to mitogens. In contrast to those normal findings was the identification of a subset of T lymphocytes in HH that formed rosettes with sheep red blood cells (SRC) at 37 degrees C in abnormally high numbers. Those lymphocytes that formed thermostable erythrocyte rosettes (TE-R) were not immature thymocytes, activated T lymphocytes, or an artifact of passive attachment of anti-SRC antibodies to the HH lymphocyte surface. Their presence did not correlate with a concentration of iron in the serum, the length of treatment, or the presence of the HLA antigen, A3. We conclude that the cellular expression of HH may be detected not as an immunological abnormality, but rather as an abnormality in receptor expression.

Antibodies, Monoclonal↗
PubMed1984

[Not Available].

Explore the source record for details and available documents.

Demography↗
PubMed1984

Genetic distances between the Utah Mormons and related populations.

Gene frequency data, consisting of six red cell antigen loci, nine electrophoretic systems, and HLA-A and -B are reported for the Utah Mormon population. These are compared statistically to gene frequencies from at U.S. population, 13 European populations, and seven populations from three religious isolates. The Mormon gene frequencies are similar to those of their northern European ancestors. This is explained by the large founding size of the Mormon population and high rates of gene flow. In contrast, the religious isolates (Amish, Hutterites, and Mennonites) show marked divergence from their ancestral populations and each other, due to isolation and random genetic drift. The HLA loci and electrophoretic loci presented here yield sets of genetic distances that are highly correlated (r = .734) and that both correspond closely to the actual geographic distances among the European populations. The genetic distances based on red cell antigen loci correspond less closely to the geographic distances and exhibit lower correlations with both the HLA and electrophoretic loci (r = .524 and r = .565, respectively).

Alleles↗