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PubMed1999

Breast cancer risk in ataxia telangiectasia (AT) heterozygotes: haplotype study in French AT families.

Epidemiological studies in ataxia telangiectasia (AT) families have suggested that AT heterozygotes could have an increased cancer risk, especially breast cancer (BC) in women. It has also been suggested that an increased sensibility of AT heterozygotes to the effect of ionizing radiation could be responsible for the increased BC risk. BC relative risk (RR) estimation in AT heterozygotes within families ascertained through AT children is presented here. Family data collected included demographic characteristics, occurrence of cancers, past radiation exposures and blood samples. DNA samples were studied using seven ATM linked microsatellites markers allowing AT haplotypes reconstitution. The relative risk of BC was assessed using French estimated incidence rates. A significant increase risk of BC is found among obligate ATM heterozygotes with a point estimate of 3.32 (P = 0.002). BC relative risk calculated according to age is significantly increased among the obligate ATM heterozygotes female relatives with an age < or = 44 years (RR = 4.55, P = 0.005). The BC relative risk is statistically borderline among the obligate ATM heterozygote female relatives with an age > or = 45 years (RR = 2.48, P = 0.08). The estimated BC relative risk among ATM heterozygotes is consistent with previously published data. However, the increased risk is only a little higher than classical reproductive risk factors and similar to the risk associated with a first-degree relative affected by BC.

Adolescent↗

PubMed1996

The triplicated alpha-globin gene locus in beta-thalassaemia heterozygotes: clinical, haematological, biosynthetic and molecular studies.

Excess alpha-globin chains play a major role in the pathophysiology of homozygous beta-thalassaemia. In beta-thalassaemia carriers a minor effect of alpha-globin chain excess is reflected in a minimal or mild anaemia without clinical symptoms. Factors that increase alpha-chain excess in heterozygotes are expected to accentuate the severity of the clinical and haematological phenotype. We report the clinical, haematological, biosynthetic and molecular data in three beta-thalassaemia heterozygotes with the rare interaction of homozygosity for alpha-globin gene triplication, and in 17 heterozygotes with a single additional alpha-globin gene. The three patients homozygous for the alpha-globin gene locus (anti 3.7 kb arrangement) had beta(0)-thalassaemia mutations and a diagnosis of thalassaemia intermedia, preserving haemoglobin levels around 7-8 g/dl. Of the 17 beta-thalassaemia heterozygotes (six children and 11 adults), 16 had severe beta-thalassaemia mutations interacting with an additional alpha-globin gene (13 with alpha alpha alpha anti-3.7 and four with alpha alpha alpha anti-4.2). Compared to simple beta-thalassaemia heterozygotes, they had lower haemoglobin levels and red cell indices, but higher alpha/beta biosynthesis, HbF levels and reticulocytes. Our results suggest that homozygous alpha-gene triplication interacts with a severe beta-thalassaemia mutation to cause an alpha-chain excess equivalent to that observed in homozygous beta-thalassaemia intermedia. In heterozygotes for severe beta-thalassaemia mutations with one additional alpha-globin gene, the alpha-chain excess causes a more pronounced degree of anaemia than is usually seen in simple beta-thalassaemia heterozygotes.

Adult↗

PubMed2000

Differential HFE allele expression in hemochromatosis heterozygotes.

BACKGROUND & AIMS: Hereditary hemochromatosis is associated with C282Y homozygosity. Some heterozygotes may also present with abnormal iron parameters. However, the precise role of H63D and C282Y mutations in iron overload is poorly understood. We investigated the level of expression of the mutated and unmutated HFE alleles in these heterozygous patients. METHODS: We studied the expression of HFE messenger RNAs in peripheral blood mononuclear cells from 34 heterozygotes using reverse-transcription polymerase chain reaction (PCR) followed by enzymatic digestion or sequence analysis of the PCR products, which allows relative quantification of mutated and unmutated transcripts. HFE proteins were quantified by Western blotting in Epstein-Barr virus-immortalized lymphocyte extracts from 2 C282Y and H63D homozygotes and a compound heterozygote. RESULTS: (187C > G; H63D) mutated transcripts predominated in H63D and compound heterozygotes and the normal transcripts in C282Y heterozygotes. The amount of HFE protein was increased in the H63D homozygotes and the compound heterozygote compared with the C282Y homozygotes. In addition, we found a new mutation at codon 282 (C282S) associated with severe iron overload. CONCLUSIONS: We demonstrate the existence of differential allelic expression of the HFE alleles, suggesting that the (187C > G; H63D) mutation plays a role in the disease expression in H63D heterozygotes, in particular when associated with environmental or host factors.

Adult↗

PubMed1977

Heterozygote detection in angiokeratoma corporis diffusum (Anderson-Fabry disease). Studies on plasma, leucocytes, and hair follicles.

Heterozygote detection for angiokeratoma corporis diffusum (Anderson-Fabry disease, ACD), an X-linked disorder of glycosphingolipid metabolism was examined using alpha-galactosidase activity, an alpha-galactosidase/beta-galactosidase activity ratios (alpha/beta ratio) in leucocytes, plasma, and hair follicles; For leucocytes, 22 obligate heterozygotes, 25 suspected heterozygotes, and 47 control subjects were studied, while for plasma, the groups were 17 obligate heterozygotes and 35 controls. The alpha/beta ratio in plasma and leucocytes was clearly a better discriminator between obligate heterozygotes and controls than alpha-galactosidase activity alone, but still failed to detect 3 obligates with leucocytes and 2 with plasma. Discrimination was not improved by joint use of plasma and leucocyte alpha/beta ratios, but was improved by measurement of hair-follicle alpha/beta ratios. The interdecile range of log (alpha-galactosidase/beta-galactosidase activity) in 20 hair follicles from each of 4 obligate and 7 suspected heterozygotes was clearly different from 11 control subjects. Accordingly, for rapid screening for carriers of ACD, we recommend use of leucocyte or plasma alpha/beta ratios which should detect greater than 85% of heterozygotes. When results are equivocal, and ancillary information suggests heterozygous status, the more time-consuming measurement of hair-follicle alpha/beta ratios is a useful additional test.

Fabry Disease↗

PubMed1991

Alcoholic liver disease in heterozygotes of mutant and normal aldehyde dehydrogenase-2 genes.

To clarify the pathogenetic role of acetaldehyde in the development of alcoholic liver disease, genotyping of aldehyde dehydrogenase-2 genes was performed and the clinical features of the alcoholic liver disease patients with different genotypes were compared. Genotyping of aldehyde dehydrogenase-2 was performed in 47 patients with alcoholic liver disease using the polymerase chain reaction and slot-blot hybridization. Of the 47 patients with alcoholic liver disease, 40 were homozygous for the normal aldehyde dehydrogenase-2 gene and the remaining seven cases were heterozygous for the normal and mutant aldehyde dehydrogenase-2 genes. No homozygote was found for the mutant aldehyde dehydrogenase-2 genes. Daily alcohol intake was less than 100 gm in all heterozygotes without relation to the type of alcoholic liver disease. On the other hand, all but four patients homozygotic for the normal aldehyde dehydrogenase-2 gene drank more than 100 gm alcohol/day. The mean daily alcohol intake in the heterozygotes was significantly lower than that in the normal homozygotes. The incidence of alcoholic fibrosis tended to be lower in the heterozygotes than in the normal homozygotes (14.2% vs. 52.5%). On the other hand, the incidence of alcoholic hepatitis and/or cirrhosis tended to be higher in the heterozygotes than in the normal homozygotes. These results indicate that alcoholic liver disease develops even with moderate amounts of alcohol intake in heterozygotes of the aldehyde dehydrogenase-2 genes, in which acetaldehyde metabolism in the liver is impaired and liver damage in the heterozygotes is more severe than that in the normal homozygotes, suggesting that habitual drinkers who are heterozygotes of the aldehyde dehydrogenase-2 genes may be at high risk for alcoholic liver disease.

Alcohol Drinking↗

PubMed1989

Heterogeneous phenotypes of platelet and plasma von Willebrand factor in obligatory heterozygotes for severe von Willebrand disease.

To characterize the heterogeneity of severe (type III) von Willebrand disease (vWD), plasma and platelet von Willebrand factor antigen (vWF:Ag) and ristocetin cofactor activity (Ricof) were measured in 28 obligatory heterozygotes (ie, parents or children of probands from 15 different kindreds with severe vWD). On the average, heterozygotes had low levels of vWF in both platelets and plasma. There was, however, considerable heterogeneity, with four distinct patterns. Eleven heterozygotes had concordant reduction of vWF:Ag and Ricof in both plasma and platelets; five had low levels of vWF:Ag and Ricof in plasma contrasting with normal levels in platelets; eight had a peculiar pattern, the reverse of the above (ie, low levels in platelets and normal levels in plasma); and in one, both vWF measurements were normal in plasma and platelets. These patterns were genetically determined: they were consistent in four couples of consanguineous heterozygotes and in two couples carrying the same gene deletion. Only the remaining three heterozygotes had no clearly identifiable pattern. Other findings of this study were that although most of the heterozygotes had normal bleeding times, the 7 of 28 who had prolonged bleeding times had concordantly low levels of vWF measurements in both plasma and platelets. In conclusion, this large series of obligatory heterozygotes provides evidence for phenotypic and genotypic heterogeneity of severe vWD.

Bleeding Time↗

PubMed2001

Proton magnetic resonance spectroscopy of Sjögren-Larsson syndrome heterozygotes.

A deficit of fatty alcohol:NAD+ oxidoreductase complex (FAO) activity has been detected in patients with the Sjögren-Larsson syndrome (SLS). A moderate decrease in FAO activity has also been reported in heterozygote SLS subjects. Abnormal peaks were detected with proton magnetic resonance spectroscopy (1H-MRS) in homozygote SLS subjects. The purpose of this study was to examine whether 1H-MRS can be used to detect metabolic and/or pathological abnormalities in heterozygote SLS subjects. Four SLS heterozygotes were examined using 1H-MRS. A moderate decrease in FAO activity was demonstrated in two of the four heterozygotes. Abnormal peaks were detected at 0.9 ppm in the spectrum from cerebral hemispheres of every heterozygote. 1H-MRS was able to detect an abnormal accumulation of fatty alcohols and lipids, which is expected to increase due to an decrease in FAO activity or dysmyelination in heterozygote SLS subjects. Thus, 1H-MRS is suggested to be a powerful tool in the screening of SLS heterozygotes.

Adult↗

PubMed1997

Compound heterozygotes for hemochromatosis gene mutations: may they help to understand the pathophysiology of the disease?

Two mutations have been described on the gene considered to be responsible for genetic hemochromatosis, the HLA-H or HFE gene. The C282Y mutation is a disease-causing mutation in most cases of genetic hemochromatosis, but involvment of the H63D substitution in the pathogenesis of the disease is unclear. Compound heterozygotes for both substitutions could help to determine whether or not the second mutation is a worsening factor when associate in trans with the C282Y mutant. We found twenty nine compound heterozygotes during DNA analysis of patients referred to our laboratory for the screening of those mutations. Clinical and biological data were obtainable for 23 of them. Compound heterozygotes could be divided into two groups: subjects with or without iron overload. Five (22%) individuals had normal ferritin levels, whereas 18 had elevated ferritin concentrations (78%). Among those 18 patients, 7 (30% of the total) had clinical and biological criteria of genetic hemochromatosis. Eleven had iron overload without all the criteria of genetic hemochromatosis. Such a high proportion of genetic hemochromatosis is not found in heterozygotes for the C282Y mutation alone neither in our series nor in the literature. Compound heterozygotes for the C282Y and the H63D mutations may have a higher risk of iron overload or genetic hemochromatosis than single heterozygotes for the C282Y mutation. We propose a schematic theoretical representation that could explain this fact at the protein level. Further fundamental studies on the protein, and clinical follow up of compound heterozygotes could help to ascertain this hypothesis.

Adult↗

PubMed1992

Heterogeneity in the clastogenic response to X-rays in lymphocytes from ataxia-telangiectasia heterozygotes and controls.

A coded analysis of X-ray-induced chromatid aberrations in lymphocyte cultures from 45 control individuals and 19 ataxia-telangiectasia (A-T) heterozygotes was performed. The distribution of chromatid breaks induced in the late G2 portion of the cell cycle by 60 cGy of X-rays appeared bimodal in the study population. In six controls (13 percent) and in 12 of 19 (63 percent) A-T heterozygotes, the yields of X-ray-induced breaks observed were within the higher mode of the distribution. However, lymphocytes from A-T heterozygotes sensitive to the induction of chromatid breaks by 60 cGy did not contain increased numbers of aberrations following exposure to 20 cGy. The radio-resistant inhibition of DNA synthesis that occurs in A-T homozygotes was not observed in heterozygotes. Co-cultivation experiments showed an increased G2 delay in lymphocytes from an A-T heterozygote whose lymphocytes contained increased X-ray-induced chromatid breaks. The results show a significant association of A-T heterozygosity with G2 chromosomal sensitivity (P less than 0.001; Wilcoxon rank sum test). The measurement of X-ray-induced breaks, however, failed to identify 37 percent of A-T heterozygotes tested. The predicted prevalence of increased sensitivity to X-rays in controls is approximately three- to 30-fold greater than the estimated frequency of A-T heterozygotes in the general population. Therefore, although the increased sensitivity to X-ray-induced chromatid breaks appears to be associated with the A-T-gene, it is not a reliable indicator of A-T heterozygosity. Genetic or environmental factors other than the A-T gene also must be involved in the increased clastogenic response.

Ataxia Telangiectasia↗

PubMed2000

Characterization of beta-galactosidase in leukocytes and fibroblasts of GM1 gangliosidosis heterozygotes compared to normal subjects.

OBJECTIVES: Characterization of beta-galactosidase in leukocytes and fibroblasts of heterozygotes for GM1 type I. DESIGN AND METHODS: Leukocyte and fibroblast beta-galactosidase activity was determined fluorimetrically using 4-methylumbelliferyl-beta-D-galactoside as an artificial substrate. Optimum pH, Km, Vmax and thermostability of the enzyme at 42 degrees C were determined. RESULTS: The leukocyte and fibroblast enzyme of heterozygotes have an optimum pH of 4.0 and 4.2, respectively. In normal subjects, the optimum pH was 4.2 in both cells, according to previous studies. The Km of the enzyme of heterozygotes was determined to be 0.65 mM in leukocytes and 0.59 mM in fibroblasts. The Vmax was determined in 167.21 nmol/h/mg of protein in heterozygotes leukocytes and 541.2 nmol/h/mg of protein in heterozygotes fibroblasts compared to 291.7 and 1768.1 nmol/h/mg of protein in controls leukocytes and fibroblasts, respectively. When leukocyte and fibroblast heterozygote beta-galactosidase was preincubated at 42 degrees C, after 80 min the residual activity was determined to be 25 to 30% of the initial activity. These results are similar to the control group. CONCLUSIONS: We have found significant differences between the two groups in some investigated parameters. Both fibroblasts and leukocytes showed a virtually similar level of reliability as source of enzyme for the detection of heterozygotes.

Cells, Cultured↗

PubMed1991

Assessment of chronic gamma radiosensitivity as an in vitro assay for heterozygote identification of ataxia-telangiectasia.

Ataxia-telangiectasia (A-T) is a rare human autosomal recessive disorder characterized by, among other symptoms, catastrophic reaction to conventional radiotherapy. A-T heterozygotes are clinically asymptomatic and their fibroblasts are intermediate in radiosensitivity between homozygotes and normals. We have attempted to identify heterozygotes by assaying for cellular hypersensitivity to chronic gamma irradiation. Cultured dermal fibroblast strains from 13 control subjects and 55 members from a large Amish pedigree segregating for A-T were assayed for loss of colony-forming ability (CFA) in response to 137Cs gamma radiation delivered at a dose rate of 0.8 cGy/min. For each strain, multiple dose-response curves were summarized in a composite D10 value (dose, in cGy, reducing colony survival to 10%). The D10's of the clinically normal controls and of those pedigree members with known A-T genotype formed a trimodal distribution, with the seven obligate heterozygotes displaying an average value (516 cGy) intermediate between that of the 10 healthy controls (797 cGy) and that of the two affected patients (154 cGy). The D10's were modeled statistically using Gaussian penetrance functions. The most parsimonious model yielded a significant difference in D10 means for heterozygotes and normal homozygotes, a significant donor age effect, but no sex effect. We compared probabilistic identification of heterozygotes based on D10 values with identification based on linkage data for two markers, THY1 and D11S144, closely linked to the A-T gene. This comparison revealed that the D10 data were appreciably less informative than the linked markers. Indeed, the extensive overlap between D10 values for heterozygotes and normal homozygotes precludes the use of postirradiation CFA for either accurate identification of heterozygotes or chromosomal mapping of the A-T gene.

Ataxia Telangiectasia↗

PubMed1987

An improved method for heterozygote detection of cystinosis, using polymorphonuclear leukocytes.

Heterozygotes for the autosomal recessive disease cystinosis are currently detected by measuring the cystine content of mixed-leukocyte preparations. The present study was designed to reassess the accuracy of this method and to determine whether measuring the cystine content of purified polymorphonuclear leukocytes would improve heterozygote detection. Blood samples were obtained from 29 obligate heterozygotes for nephropathic cystinosis, one obligate heterozygote for benign cystinosis, and 18 individuals presumed to be normal. When the cystine content of mixed-leukocyte preparations was measured, three heterozygote values overlapped the normal range. When polymorphonuclear-leukocyte cystine content was measured, no heterozygote values were within the normal range. Measurement of the cystine content of purified preparations of polymorphonuclear leukocytes affords a simple method that improves the sensitivity of heterozygote detection for cystinosis.

Cysteine↗

PubMed1992

Elevated sulfatide excretion in heterozygotes of metachromatic leukodystrophy: dependence on reduction of arylsulfatase A activity.

Sulfatide excretion in urine and arylsulfatase A (ASA) activity in leukocytes were determined in 10 homozygotes of metachromatic leukodystrophy (MLD), 7 obligate and 5 facultative MLD heterozygotes, 6 low ASA subjects (not related to MLD homozygotes), and in 9 controls. As compared to controls (sulfatides: 0-2 nmol/mg lipid; ASA: 101-287 nmol p-nitrocatechol/mg protein/hr), MLD homozygotes displayed highly increased sulfatide excretions (27-280 nmol) and low residual ASA activities (0-13 nmol). Of 12 MLD heterozygotes (ASA: 18-87 nmol) 10 showed increased sulfatides (3-24 nmol). All heterozygotes with ASA activity < 60 nmol (n = 8) had elevated sulfatide excretions (4-24 nmol). Thus, reduction of ASA activity below 40% of the mean value of controls seems to be the critical threshold for elevated sulfatide excretion in MLD heterozygotes. The low ASA subjects (ASA in the heterozygote range) excreted sulfatides in the control range, even those with ASA activities < 60 nmoles (n = 3; including a definite homozygote for ASA-pseudodeficiency; ASA:25 nmol). Statistical evaluation of sulfatide excretion and ASA activity in all subjects (n = 37) revealed a significant inverse relation (Spearman rank correlation; R = 0.8278, P < 0.001). The finding of elevated sulfatide excretion in certain MLD heterozygotes might point to increase of sulfatides also in the nervous system.

Adult↗

PubMed1994

Relationship of expansion of CGG repeats and X-inactivation with expression of fra(X)(q27.3) in heterozygotes.

Expression of the fragile site Xq27.3 was investigated in 82 heterozygotes (58 normal and 24 mentally impaired) diagnosed by DNA analysis. EcoRI and EagI DNA digests were probed with StB12.3. This allowed the detection of the expansion of the CGG repeat of the FMR1 gene and the methylation pattern of the adjacent CpG island. Heterozygotes with delta < or = 400 bp (52/82) were all mentally normal and manifested fra(X) in less than 3% of the cells or did not express it. Unmethylated mutant alleles were always observed. About two thirds of females with delta > 500 bp (21/30) showed fra(X) frequencies above 3% (3 normal and 18 mentally impaired). Lower frequencies of fra(X) or negative results were observed in the remaining 9 females (3 normal and 6 affected). The large mutant alleles were always methylated. Therefore, while delta < or = 400 bp is always associated with negative or low expression of fra(X), larger expansions are not present exclusively in heterozygotes with high frequencies of fra(X). In 25 of 30 heterozygotes with delta > 500 bp, active and inactive normal alleles were observed. Three fra(X)-negative or low manifesting heterozygotes showed completely skewed X-inactivation, with the normal allele either active or inactive. Two females with high frequencies of fra(X) always had the normal allele inactivated. Densitometry studies showed no difference in the inactivation of the normal allele between heterozygotes who manifested fra(X) or not. Thus fra(X) expression does not seem to be influenced by X-inactivation.

Chromosome Fragile Sites↗

PubMed2001

Cancer risk in heterozygotes for ataxia-telangiectasia.

Epidemiological studies have suggested that ataxia-telangiectasia (AT) heterozygotes have a predisposition to cancer, especially breast cancer in women. Now, haplotyping can identify heterozygotes for AT mutation (ATM) in AT families, allowing the risk of cancer associated with ATM heterozygosity status to be better assessed. We report a family study of AT patients, in which we estimated the risk of cancer according to ATM heterozygosity status. We analyzed demographic characteristics and occurrence of cancer in 1,423 relatives of AT patients. Haplotyping was performed in living relatives. The probability of being heterozygotes for ATM was calculated for deceased relatives. The risk of developing cancer was estimated in the cohort of relatives, and expected numbers of cancer cases were calculated from French age period-specific incidence rates. The number of cancers at all sites in the total population of relatives was not higher than expected. However, significant heterogeneity was found according to ATM heterozygosity status. This is mainly due to the increased risk of breast cancer previously observed in obligate heterozygotes. In obligate heterozygotes, relative risk (RR) was non-significantly increased for thyroid cancer, leukemia and liver cancer. Risks of ovarian, lung, pancreatic, kidney, stomach and colorectal cancers were non-significantly increased in the group with 0.5 probability of being heterozygotes. The RR was not significantly increased for any site of cancer, except for breast. Therefore, there is no evidence that specific screening of relatives of AT patients would be justified at particular sites other than the breast. However, the amplitude of the risk of breast cancer estimated in heterozygous women does not appear to justify a separate screening program from that already available to women with a first-degree relative affected by breast cancer.

Ataxia Telangiectasia↗

PubMed1992

Heterozygote deficiency, population substructure and their implications in DNA fingerprinting.

Substructured populations exhibit an overall deficiency of heterozygosity whose proportional magnitude depends on the nature of substructuring, i.e., the number of subpopulations (s), their time of divergence (t) from the ancestral population, and the rate of gene flow amongst them (m). Since apparent heterozygote deficiency could be caused by many factors other than population substructuring, one must examine the nature of substructuring that could produce the observed extent of heterozygote deficiency, in order to infer the substructuring from an observed heterozygote deficiency. Using the equivalence of proportional heterozygote deficiency and the coefficient of gene differentiation (GST), we can generate isolines of GST as functions of s, t (in units of 2Ne generations, Ne being the effective population size) and m. Analytical results suggest that large GST values cannot be reached by substructuring alone, unless the number of subpopulations are large and they remain isolated over a long period of time. Application of the theory to population data on six variable number of tandem repeats (VNTR) loci in US Caucasians and US Blacks demonstrates that the observed heterozygote deficiencies at these loci cannot be explained by substructuring within these populations alone. This is so because such large values of GST (3%-10%) would require an absence of gene exchange between the subpopulations and a divergence time from each other of at least 25,000 years ago, neither of which is compatible with the demography and ethnohistory of US Caucasians and Blacks. In contrast, the inability to detect extreme-sized alleles and/or incomplete resolution of nearly similar-sized alleles following Southern gel electrophoresis could easily explain the observed heterozygote deficiencies. The implications of these results are discussed in the context of the forensic use of DNA-typing data, and justify the employment of population genetic principles in forensic genetics.

Black People↗

PubMed1995

Selection against blood cells deficient in hypoxanthine phosphoribosyltransferase (HPRT) in Lesch-Nyhan heterozygotes occurs at the level of multipotent stem cells.

Lesch-Nyhan syndrome is caused by a severe genetic deficiency of hypoxanthine phosphoribosyltransferase (HPRT) and is characterized by central nervous system disorders, gout, and in some cases, macrocytic anemia. Women heterozygous for HPRT deficiency are healthy but their somatic cells are mosaic for enzyme deficiency owing to random inactivation of the X chromosome. Frequencies of red blood cells and T cells deficient in HPRT are significantly lower than the expected 50% in heterozygotes, suggesting that HPRT-negative blood cells are selected against in heterozygotes. To determine at which stage of hematopoiesis such selection occurs, we determined the frequencies of HPRT-negative T, B and erythroid precursor cells in three heterozygotes. Since the cloning efficiencies of T and B cells and colony forming efficiency of burst-forming unit erythroid (BFU-E) for sample from Lesch-Nyhan patients were similar to those of normal cells, HPRT deficiency does not seem to render the differentiated cells less efficient for proliferation. However, the frequencies of HPRT-negative T and B cells, and BFU-E were all less than 10% in each of the three heterozygotes. Although the frequencies of HPRT-negative cells showed tenfold variations between the heterozygotes, each heterozygote had similar frequencies of HPRT-negative cells in the three cell types. These results suggest that HPRT is important at early stages of hematopoiesis, but less so after the cells have differentiated into T cells, B cells and erythroid precursor cells.

Adult↗

PubMed1976

Isoenzymes of serum N-acetyl-beta-D-glucosaminidase in the I cell disease heterozygote.

Serum N-acetyl-beta-D-hexosaminidase is compared quantitatively and qualitatively in 14 obligate heterozygotes for the mutant gene causing I cell disease (ICD) or mucolipidosis II and in 31 normal controls. The average specific activity in either group is significantly different but reliable heterozygote detection cannot be achieved because of some overlapping of the ranges of individual results. Fractionation of the enzyme either by DEAE cellulose column chromatography, or by heat inactivation, yields a typical average result for each genotype. Also, mere expression of the various components as percentages of the total activity is not useful for certain identification of the ICD heterozygote. There is considerable overlapping of the percents hexosaminidase I1 and A in both groups of sera. If enzymatic hydrolysis by any component is expressed as a partial activity, a much better though not absolute distinction between the ICD heterozygote and the normal control becomes possible. Only the latter way of expression of hexosaminidase results makes distinction between the ICD heterozygote and the Tay-Sachs heterozygote very probable.

Acetylglucosaminidase↗