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PubMed1982

Detection of heterozygotes in maple-syrup-urine disease: measurements of branched-chain alpha-ketoacid dehydrogenase and its components in cell cultures.

To detect heterozygotes for maple-syrup-urine disease (MSUD), activities of branched-chain-alpha-ketoacid (BCKA) dehydrogenase and its components in skin fibroblasts of two obligatory heterozygotes and amnion cells of a fetus at risk were measured. Intact heterozygous cells were found to decarboxylate [1-14C] alpha-ketoisovalerate at rates equal to or only slightly lower than normal subjects. The inability to differentiate heterozygotes from normals with the intact cell assay confirms earlier studies with intact leukocytes using [1-14C]leucine as substrate. By contrast, measurements of BCKA dehydrogenase activity with disrupted cell suspensions showed MSUD heterozygotes with 30%--60% of normal activity. Moreover, biphasic kinetics in heterozygous cells were observed with increasing substrate concentrations. The altered biphasic kinetics probably reflect expression of the normal allele in the early hyperbolic portion of the curve of the mutant allele in the later secondary rise at high substrate concentrations. Assays of component activities showed concordant E1 decarboxylase deficiency in both heterozygous- and homozygous-affected cells, whereas the E3, dihydrolipoyl dehydrogenase-component, activity was normal. The above results taken together appear to provide an approach to detection of the heterozygote in MSUD.

3-Methyl-2-Oxobutanoate Dehydrogenase (Lipoamide)↗
PubMed1998

Identification of heterozygotic carriers of 21-hydroxylase deficiency: sensitivity of ACTH stimulation tests.

Congenital adrenal hyperplasia due to 21-hydroxylase deficiency is a common autosomal-recessive disorder. To ascertain carrier status, adrenocorticotropin (ACTH) stimulation tests are often used. To determine the sensitivity of ACTH stimulation to detect heterozygotes and to correlate stimulated 17-hydroxyprogesterone responses with molecular genotype, we compared molecular genetic analysis of the 21-hydroxylase (CYP21) gene with 17-hydroxyprogesterone responses at 30 min in 51 individuals. Molecular genotype analysis and ACTH stimulation tests were performed in healthy volunteers (n = 20) and relatives of patients with congenital adrenal hyperplasia (n = 31). Polymerase chain reaction (PCR) amplification, single-strand conformational polymorphism (SSCP) analysis, allele-specific oligonucleotide hybridization (ASOH) analysis, and restriction fragment length polymorphism (RFLP) analysis were utilized to screen for 14 CYP21 mutations which account for >90% of the mutations associated with 21-hydroxylase deficiency. Molecular genotype analysis classified 28 individuals as heterozygotic carriers and 23 individuals as normal for all mutations tested. As a group, the heterozygotes had significantly greater stimulated 17-hydroxyprogesterone responses at 10 and 30 min (P < 0.0005). However, on an individual basis, 14/28 (50%) genotyped heterozygotic carriers had stimulated 17-hydroxyprogesterone concentrations, 17-hydroxyprogesterone/cortisol ratios, and 17-hydroxyprogesterone incremental elevations indistinguishable from the genotyped normal individuals. Thus, a normal 17-hydroxyprogesterone response to ACTH stimulation testing does not exclude carrier status for 21-hydroxylase deficiency. Molecular genotype analysis is a more reliable method to determine 21-hydroxylase heterozygotes.

17-alpha-Hydroxyprogesterone↗
PubMedDate not supplied

HLA typing in idiopathic hemochromatosis: distinction between homozygotes and heterozygotes with biochemical expression.

In a study of 20 families with idiopathic hemochromatosis, relatives of probands were classified as either homozygous, heterozygous, or normal according to their HLA phenotype. An abnormality in the serum iron concentration, total iron-binding capacity, or serum ferritin concentration was present in all homozygotes and in 25% of heterozygotes. In heterozygotes, the mean total iron-binding capacity was significantly decreased, and the mean hepatic iron concentration was significantly increased compared to normals. However, in contrast to homozygotes, clinical evidence of iron overload was not observed in heterozygotes, and there was no biochemical or histological evidence of liver disease resulting from excessive iron stores. Progressive iron overload did not develop in 44 heterozygotes who were studied for up to 16 yr.

Adolescent↗
PubMedDate not supplied

Tubular aggregates in murine dystrophy heterozygotes.

Heterozygous dystrophic mice (strain 129 ReJ dy/+) were studied to determine the morphological changes that are characteristic of the heterozygote state. The morphology of the muscle in 35 heterozygotes (+/?) was compared with that of 35 homozygotes (dy/dy) and 20 normal controls (+/+). Muscle was examined with light microscopy, standard histochemical techniques, and electron microscopy. Few abnormalities were detected with light microscopy or with histochemistry. With electron microscopy, some slight nonspecific evidence of muscle damage in the form of focal myofibrillar degeneration was seen in all of the heterozygotes. The striking abnormality, however, was the presence of tubular aggregates in type 2 fibers in 60% of the heterozygotes. Tubular aggregates were not found in homozygous dystrophic mice or in normal controls. The significance of this finding is discussed and it is suggested that tubular aggregates may represent lateral sac dilatation and infolding.

Animals↗
PubMed1990

Selective advantage of fra (X) heterozygotes.

The high incidence of the fra (X) syndrome (about 1:2000 male newborns) requires an explanation in view of the low fitness of mentally retarded hemizygous males and heterozygous females. In the past, it has been proposed that the mutation rate may be unusually high, and that mutations occur exclusively in male germ cells. According to an alternative hypothesis, a moderately high mutation rate might combine with a selective advantage of clinically unaffected heterozygotes. In earlier studies, such a combined hypothesis was shown to lead to plausible implications regarding mutation rate and fitness. Moreover, a mutation rate in male germ cells of the magnitude required by the exclusive mutation hypothesis was excluded by studies on comprehensive pedigree data. In this third study in the series, an increased fitness of heterozygous females is demonstrated directly by a comparison of the reproductive performance of heterozygotes with that of adequate controls (mothers and grandparents of Down's syndrome patients). Since, average numbers of children have decreased during recent decades in populations of industrialized countries, heterozygotes (mothers of affected probands and their female relatives in their own generation) were subdivided into those born before and after 1940. Moreover, sibship sizes of probands' mothers and fathers were analyzed separately for family branches in which the fra (X) trait segregated (mostly the maternal branch), or did not segregate (in most instances the paternal branch). In all four categories reproductive performance in heterozygotes was found to be higher than in the controls. This difference was significant statistically for two of the four groups; it was small and nonsignificant only for the parental family branch in which the fra (X) mutant did not segregate and for mothers born after 1940. Fitness estimates ranged between 1.11 and 1.36. A higher incidence of dizygotic twinning suggests a biological component for this increased fertility. On the other hand, fra (X) families have a significantly lower social status than the controls. This suggests a socio-psychological component of their higher fertility. Apparently, both components contribute to their fertility; at present, their relative importance cannot be assessed.

Birth Rate↗
PubMed1990

Cytogenetic characterization of ataxia telangiectasia (AT) heterozygotes using lymphoblastoid cell lines and chronic gamma-irradiation.

Lymphoblastoid cell lines (LCLs) derived from two patients identified as ataxia telangiectasia (AT), two obligate AT heterozygotes and two controls (healthy subjects with no known genetic disease or relationship to AT patients) were compared with respect to the induction of chromosomal breaks by acute and chronic gamma-irradiation. Although there was a considerable increase in the frequency of chromosomal breaks per cell in the LCLs of AT patients resulting from acute irradiation, the small increase occurring in the LCLs of the AT heterozygotes made it difficult to distinguish them from the controls. Following chronic gamma-irradiation, however, the frequency of chromosomal breaks per cell in the LCLs of the AT heterozygotes occupied a significantly distinct position from that of the controls. These observations suggested that the use of chronic irradiation may be a better choice in the cytogenetic characterization of AT heterozygotes.

Ataxia Telangiectasia↗
PubMed1990

Fetal hemoglobin in normal adults and beta-thalassemia heterozygotes.

A recently developed high performance liquid chromatographic (HPLC) procedure using a weak cation exchanger (PolyCAT) in columns of different sizes was used to quantify fetal hemoglobin (HbF) in blood of normal adults and beta-thalassemia (beta-thal) heterozygotes with ten different types of mutations. Preparative PolyCAT-HPLC greatly facilitated the characterization of isolated HbF, i.e., the determination of the relative quantities of the G gamma and A gamma chains. The method is accurate and allows quantitation of Hb F at the 0.5% level; preparative PolyCAT-HPLC allows isolation of (nearly) pure Hb F from blood samples with low (less than 1%) Hb F. Adult Hb F levels were determined in 69 normal adults (including 24 diabetics); Hb F levels fell below 1% except for subjects with abnormal -- G gamma -- G gamma -- arrangement and a C----T mutation at position -158 relative to the Cap site of both G gamma genes. The effect of the same mutation in the normal -- G gamma -- A gamma-arrangement was variable. Certain beta-thal mutations (namely, those at positions -29; -88; IVS-I-1; IVS-II-1) were associated with high Hb F levels in heterozygotes, while those at nucleotide (nt) positions IVS-I-6; IVS-I-110; codon 24; codon 39; codons 41/42; IVS-II-745 were not. G gamma values varied and often fell into two groups (high G gamma and low G gamma); high G gamma values were not associated with high Hb F values. The chromatographic procedure is ideally suited for Hb A2 quantitation. Average values of Hb A2 in beta-thal heterozygotes with any one of nine of the ten mutations were twice that of normals; the one exception was the beta-thal heterozygote with the IVS-I-6 (T----C) mutation with an average low Hb A2 value of 3.6%.

Adolescent↗
PubMed1978

Human erythrocyte pyruvate kinase deficiency: the use of a kinetic study of mutant enzymes for the detection of heterozygotes.

Erythrocyte pyruvate kinase (PK) deficiency was detected in a boy of dutch origin. Immunologic, electrophoretic, and kinetic studies of the enzymes of propositus and the members of his family demonstrated that the boy was heterozygote for two different mutant PK alleles. The mutant enzyme, for which his mother was heterozygote, was characterized by a lower immunologic specific activity, a decreased affinity for the substrate phospho-enol-pyruvate, and a loss of homotropic interactions toward this substrate, an increased affinity toward the allosteric inhibitor MgATP2-, a decreased affinity for the activator fructose-1,6-diphosphate, and a lowered pH optimum. Electrophoresis, Km app. for MgADP, and the reactivity toward the purine nucleotide substrate analogues were normal. The mutant enzyme for which his father was heterozygote was characterized by a decreased affinity for the substrate phospho-enol-pyruvate and a loss of homotropic interactions toward this substrate. All other parameters mentioned above were normal. The use of a kinetic study of mutant enzymes for the detection of heterozygotes is discussed.

Adolescent↗
PubMed1986

In vivo chromosomal instability in ataxia-telangiectasia homozygotes and heterozygotes.

The exfoliated cell micronucleus test was used to monitor in vivo chromosomal instability in a population comprised of five ataxia-telangiectasia (A-T) homozygotes and seven obligate heterozygotes (parents of A-T patients). This assay was previously validated as a procedure for quantifying non-invasively carcinogen-induced chromosomal aberrations occurring in vivo in epithelial tissues of both the oral cavity and the urinary bladder. The procedure involved taking air-dried smears of three sites in the oral cavity of each examined individual. Desquamated urinary bladder cells were collected by centrifugation of freshly voided urine samples. Frequencies of exfoliated cells in these preparations were determined and compared with control values (individuals with no genetic chromosomal instability and no known carcinogen exposure) for these sites. Exfoliated cell micronucleus (MEC) frequencies were elevated 5- to 14-fold in samples from the A-T homozygotes. This elevation in MEC frequency occurred for both the oral cavity and urinary bladder. Five out of the seven obligate A-T heterozygotes had an elevated MEC frequency in samples from the oral cavity. In addition, all examined urine samples from A-T heterozygotes contained an elevated percentage of micronucleated cells. These data suggest that this assay is suitable for in vivo monitoring of groups of individuals in which genetically produced chromosomal damage occurs. The possibility of A-T heterozygote detection with this simple procedure is of particular significance, since such individuals are believed to comprise up to 1% of the general population, and have been identified as being at elevated risk for cancer.

Ataxia Telangiectasia↗
PubMed1989

Heterogeneity of chromosomal breakage levels in epithelial tissue of ataxia-telangiectasia homozygotes and heterozygotes.

The objective of this study was to obtain an estimate of the frequency distribution of spontaneous chromosomal breakage occurring in vivo in oral epithelia of 20 ataxia-telangiectasia patients (A-T homozygotes) and 26 parents (A-T obligate heterozygotes). Samples of exfoliated cells were obtained from each individual by swabbing the oral cavity and preparing air-dried slides. The percentage of exfoliated cells with micronuclei (MEC frequency) was used as an in vivo indicator for the amount of chromosomal breakage occurring in the tissue. As a population group, MEC frequencies of the A-T patients differed significantly from controls (mean for A-T patients, 1.51; for controls, 0.29; P less than 0.01). However, the values observed in individual patients ranged from MEC frequencies 10- to 12-fold above control values, to frequencies overlapping the upper values observed in the controls. Similarly, MEC frequencies observed among the A-T heterozygotes differed significantly from controls (mean for A-T heterozygotes, 1.02, mean for controls, 0.29; P less than 0.01). However, only 16 of the 26 individuals sampled had MEC frequencies greater than 0.5%, the 90th percentile for controls (compared with 16 of the 20 A-T patients examined). Of the A-T patients 11 had been previously assigned to complementation groups on the basis of sensitivity to x-irradiation. Seven of the patients belonged to group A and had MEC frequencies ranging from 0.3% to 1.9% with the remaining patients belonging to group C with MEC frequencies of 0.2% to 0.9%. The data presented in this paper suggest that although levels of spontaneous breakage in epithelial tissues of A-T patients and A-T obligate heterozygotes are often significantly elevated, this is not the case in all individuals.

Adolescent↗
PubMed1988

Electrophysiological findings of neuronal ceroid lipofuscinosis in heterozygotes.

Nineteen obligate heterozygotes, 8 individuals at risk of being heterozygote, and 10 patients afflicted with four different forms of neuronal ceroid lipofuscinosis were examined electrophysiologically. The group of obligate heterozygotes was compared to age-matched control groups. Statistically significant differences were found between scotopic b-wave amplitudes, P-ERG amplitudes, and EOG light peaks of the obligate carriers of the juvenile type and the control subjects. The photopic L-ERGs and the latencies of the VEPs were mostly within the normal range. The findings represent the first evidence of functional ophthalmological changes in obligate carriers of neuronal ceroid lipofuscinosis and demonstrate that heterozygotes with certain hereditary autosomal recessive diseases may manifest subtle functional signs.

Adolescent↗
PubMed2001

A comparative study of Greek nondeletional hereditary persistence of fetal hemoglobin and beta-thalassemia compound heterozygotes.

The coexistence of beta- and gamma-globin gene mutations in the compound heterozygous state presents a rare in vivo model that provides important data on gene regulation of clinical interest. In this unique comparative study we present the hematological, biosynthetic, and molecular data from six adult compound heterozygotes for the Greek nondeletional hereditary persistence of fetal hemoglobin (nd-HPFH, Agamma-117 G-->A) and four frequent beta-thalassemia mutations (IVS I-110 G-->A, Cd 39 C-->T, IVS I-1 G-->A, and IVS I-6 T-->C) found in the Hellenic population. Fetal hemoglobin (HbF) levels were found to be considerably higher (25-50%) than in 19 Greek nd-HPFH heterozygotes (HbF=9.7+/-1.7%) and, interestingly, to depend on the type of the respective beta-thalassemia mutation, in trans to the nd-HPFH allele. All cases presented a typical beta-thalassemia heterozygote's phenotype despite the increased HbF and the normal HbA2 levels, as indicated by both the hematological indices and the biosynthetic ratios. These data were compared with those from two unique cases of Greek origin: a homozygous case of the Greek nd-HPFH and a compound heterozygote with HbS. Our data suggest that in these compound heterozygous cases the beta-thalassemic chromosome indirectly determines the final outcome of the gamma- and of the in cis beta-globin gene expression, most likely at the post-transcriptional level.

Adult↗
PubMed2004

Heterozygote advantage fails to explain the high degree of polymorphism of the MHC.

Major histocompatibility (MHC) molecules are encoded by extremely polymorphic genes and play a crucial role in vertebrate immunity. Natural selection favors MHC heterozygous hosts because individuals heterozygous at the MHC can present a larger diversity of peptides from infectious pathogens than homozygous individuals. Whether or not heterozygote advantage is sufficient to account for a high degree of polymorphism is controversial, however. Using mathematical models we studied the degree of MHC polymorphism arising when heterozygote advantage is the only selection pressure. We argue that existing models are misleading in that the fitness of heterozygotes is not related to the MHC alleles they harbor. To correct for this, we have developed novel models in which the genotypic fitness of a host directly reflects the fitness contributions of its MHC alleles. The mathematical analysis suggests that a high degree of polymorphism can only be accounted for if the different MHC alleles confer unrealistically similar fitnesses. This conclusion was confirmed by stochastic simulations, including mutation, genetic drift, and a finite population size. Heterozygote advantage on its own is insufficient to explain the high population diversity of the MHC.

Animals↗
PubMed1975

Polyamine alterations in blood of male homozygotes and heterozygotes for cystic fibrosis.

The polyamines, spermidine and spermine, have been measured in whole blood extracts from control volunteers, patients with cystic fibrosis, and obligate cystic fibrosis heterozygotes. Male homo- and heterozygotes for cystic fibrosis exhibit a consistent and significant decrease in blood spermine resulting in an elevated spermidine/spermine ratio when compared to control males. In contrast, control females exhibited reduced spermidine and spermine levels as compared to control males. Blood from female cystic fibrosis homo- and heterozygotes showed similar results. The sex difference is probably due to fluctiations of blood polyamines during the menstrual cycle. Abnormal polyamine levels are the first observation of an alteration of a low molecular weight metabolite characteristic of both male homo- and heterozygotes for cystic fibrosis.

Cystic Fibrosis↗
PubMed1976

Biokinetics of galactose in the homozygotes and heterozygotes of both forms of galactosemia.

41 heterozygoes and 4 homozygotes with a deficiency of galactose 1-phosphate uridyl transferase and also 3 heterozygotes and 1 homozygous patient with galactokinase deficiency were subjected to intravenous galactose loading tests with a dose of 350 mg/kg body weight in order to answer the question whether it is possible to detect the heterozygotes of both types of galactosemia by this method. For comparison, 38 healthy children and adolescents, 24 children with epidemic hepatitis and 4 children with cirrhosis of the liver, which was verified by histology, were included in the study. The elimination half-life (and also the other pharmacokinetic parameters as inaugurated by Dost) was the same for all the heterozygotes for both types of galactosemia almost without exception, and for the healthy cs, children in the acute stages of hepatitis and patients with cirrhosis of the liver was prolonged 2 to 5 times the normal. In patients with hepatitis, however, the elimination half-life was normal before the transaminases. Accordingly, the galactose clearance was decreased to half and one-fourth of the normal. Hence, heterozygotes with galactosemia cannot be detected with galactose loading tests.

Adolescent↗
PubMed1977

Excretion of galactitol in the urine of heterozygotes of both forms of galactosemia.

In 36 heterozygotes with Gal-1-PUT deficiency and 3 heterozygotes with galactokinase deficiency galactitol (and galactose) was determined in the urine 2 and 4 h after an intravenous injection of 350 mg galactose/kg body weight (maximum dosis in adults 16 g). For the sake of comparison 10 healthy children and 5 adults, also 4 homozygotes with Gal-1-PUT deficiency and one sick child with galactokinase deficiency were included in this study. The heterozygotes with Gal-1-PUT deficiency demonstrated the same galactitol excretion as the healthy probands, while heterozygotes with galactokinase deficiency excreted a four-fold higher quantity of galactitol than the healthy and heterozygous probands of Gal-1-PUT deficiency. The child with the galactokinase deficiency excreted galactitol for a period of more than 24 h. These results are discussed.

Galactose↗
PubMed1987

Serum concentrations of a granulocyte-derived calcium-binding protein in cystic fibrosis patients and heterozygotes.

Serum samples from cystic fibrosis homozygotes and heterozygotes contain elevated levels of a protein, known as cystic fibrosis antigen, which is synthesized primarily in granulocytes. We have produced monoclonal antibodies against cystic fibrosis antigen and developed a sensitive two-site immunoassay. Antigen levels were evaluated in serum samples from 50 cystic fibrosis homozygotes, 34 heterozygotes, 60 healthy controls and 25 disease controls. Simultaneous measurement was made of another granulocyte-derived serum protein, lactoferrin, and also of the acute-phase reactant, C-Reactive Protein. Attempts to use the concentrations of cystic fibrosis antigen in serum to distinguish cystic fibrosis patients from heterozygotes were unsuccessful, even when these concentrations were expressed as a ratio with lactoferrin or with C-Reactive Protein. However, examination of the ratio of cystic fibrosis antigen to lactoferrin in serum samples from cystic fibrosis heterozygotes suggests that there is some specific association between this antigen and the cystic fibrosis gene.

Antibodies, Monoclonal↗
PubMed1990

Decreased xanthine oxidase activities and increased urinary oxypurines in heterozygotes for hereditary xanthinuria.

Two brothers with hereditary xanthinuria (xanthine oxidase deficiency) and several members of their family were studied. In both subjects, plasma and urinary concentrations of uric acid were low whereas xanthine and hypoxanthine concentrations were markedly elevated. Xanthine oxidase activity was virtually absent in the patients' duodenal mucosa, a finding that established the diagnosis of hereditary xanthinuria. In their parents (obligate heterozygotes), the duodenal xanthine oxidase activity was about 50% of that in control subjects (father 9.3 and mother 12.8 mU/g tissue compared with 21.3 +/- 5.0 mU/g tissue, mean +/- SD). The residual xanthine oxidase from the parents exhibited normal kinetics with respect to hypoxanthine. The parents' urinary xanthine and hypoxanthine concentrations were significantly greater than those of control subjects, while their plasma concentrations of oxypurines were normal. Similar findings were observed in at least 6 other relatives, a finding that suggested that they were heterozygotes. This study suggests that obligate hereditary xanthinuria heterozygotes have only 50% of the xanthine oxidase activity of controls; this deficiency results in a partial metabolic blockage at this enzymatic step in heterozygotes.

Adult↗