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RATIONALE: Lipoprotein lipase (LPL) X447 homozygotes are characterized by enhanced conversion of TRL apoB100. Here, we set out to investigate whether this LPL variant is also associated with enhanced apoB48 clearance. Therefore, we evaluated apoB48 kinetics in X447 homozygotes in the fed state by infusion of isotope L-[1-(13)C]-valine and subsequent compartmental modeling. METHODS AND RESULTS: ApoB48 metabolism was assessed in five X447 homozygotes (X/X genotype) and five S447 homozygotes (S/S genotype). Subjects were continuously fed and received infusion of stable isotope L-[1-(13)C]-valine. Results were analyzed by SAAM II modeling. Fasting (2.4-fold, p=0.02) as well as non-fasting (1.6-fold, p=0.09) apoB48 concentration was increased in the X447 homozygotes compared to S447 homozygotes. In addition, the X447 homozygotes exhibited a 1.7-fold higher apoB48 poolsize (p=0.04). Interestingly, apoB48 fractional catabolic rate (FCR) was 1.9-fold higher (p=0.007) and apoB48 synthesis was more than two-fold higher (p=0.006) in the X447 homozygotes compared to S447 homozygotes. CONCLUSION: In the present study, we show that X447 homozygotes exhibit enhanced apoB48 clearance. Previously, these homozygotes were shown to present with enhanced apoB100 TRL conversion. Combined, this LPLS447X gain of function variant affects apoB48 as well as apoB100 TRL metabolism.
BACKGROUND: In NcoI restriction fragment length polymorphism analysis of tumor necrosis factor-beta (TNF-beta) gene, the frequency of 10.5-kb homozygote is low in patients with lung cancer and is associated with a better prognosis. These results should be examined in other malignancies. METHODS: Using polymerase chain reaction, the authors performed NcoI restriction fragment length polymorphism analysis in 152 patients with gastric cancer, in 69 patients with benign gastric lesion, and in 141 healthy volunteers. RESULTS: In 3-year survival, the 10.5-kb homozygote showed a better prognosis (87.1%) than other alleles (5.5-kb homozygote, 52.5%; heterozygote, 79.1%), and there was a statistically significant difference between the 10.5-kb homozygote and the 5.5-kb homozygote. In 3-year survival for Stages III and IV, the 10.5-kb homozygote also showed a better prognosis (64.9%) than other alleles (5.5-kb homozygote, 16.7%; heterozygote, 41.4%). There were statistically significant differences (10.5-kb homozygote vs. 5.5-kb homozygote, P < 0.01; heterozygote vs. 5.5-kb homozygote, P < 0.05). There was a statistical difference between all patients and Stages III and IV (P < 0.05). CONCLUSIONS: The 10.5-kb homozygote of TNF-beta gene is associated with a prolonged survival in patients with gastric cancer, as has been shown in the patients with lung cancer.
Silver homozygous quail was recently reported to have mutations in Mitf gene. Although numerous mutations in Mitf gene have been reported in mice, no mutations corresponding to the mutation in the homozygous silver (B/B) quail in Mitf gene have been reported to cause defects in pigmentation and bone. Therefore, we investigated the bones of the B/B homozygotes. Comparison of the bones of the B/B homozygotes with those of wild-type by X-ray examination revealed osteopetrosis in the long bones of B/B homozygotes. However, osteopetrosis in B/B homozygotes was less severe than that observed in mi/mi mice. Histological examination showed that there were less TRAP-positive multinucleated cells in the trabecular bones in B/B homozygote tibia than in the wild type. In vitro osteoclastogenesis study also suggested that formation of TRAP-positive multinucleated cell was suppressed in the marrow cells of the long bones of the B/B homozygotes. Furthermore, overexpression of chicken Mitf via retroviral transfection into B/B homozygote bone marrow cells in cultures increased the number of TRAP-positive cells 2-3 fold more than that in control. These results indicated that in addition to the previously reported defect in melanogenesis, osteoclastogenesis was inhibited in B/B homozygotes. These results indicate that the novel mutations in Mitf gene observed in the B/B homozygote quail impair osteoclastic bone resorption.
PURPOSE: To study the clinical outcomes of subjects who are homozygous for the C282Y mutation of the hemochromatosis gene. SUBJECTS AND METHODS: All patients referred to a tertiary referral centre for hemochromatosis were included. The study also included 16 C282Y homozygotes detected in a population screening study. RESULTS: The study comprised 277 C282Y homozygotes, including 16 nonexpressing C282Y homozygotes. The mean follow-up period was 7.3 years (range zero to 44 years). The actuarial survival rates of C282Y homozygotes at five, 10 and 20 years were 95%, 93% and 66%, respectively. Life-threatening diseases (cirrhosis, hepatocellular carcinoma, diabetes, heart disease) were present in 36% of male C282Y homozygotes and 19% of female C282Y homozygotes. Cirrhosis of the liver and diabetes were the major clinical symptoms affecting long term survival. Only one nonexpressing homozygote required venesection therapy during the follow-up period. CONCLUSIONS: Long term survival is excellent in C282Y homozygotes diagnosed and treated before the development of cirrhosis and diabetes.
We measured the percent absorption, turnover, and distribution of campestanol (24-methyl-5alpha-cholestan-3beta-ol) in a sitosterolemic homozygote, her obligate heterozygous mother, and three healthy human control subjects. For reasons relating to sterol hyperabsorption, the homozygote consumed a diet low in plant sterols that contained campestanol at about 2 mg/day. The heterozygote and three control subjects were fed a diet supplemented with a spread that contained campestanol at 540 mg/day and sitostanol (24-ethyl-5alpha-cholestan-3beta-ol) at 1.9 g/day as fatty acid esters. Plasma campestanol concentrations determined by capillary gas-liquid chromatography were 0.72 +/- 0.03 mg/dl in the homozygote, 0.09 +/- 0.04 mg/dl in the heterozygote, and 0.05 +/- 0.03 mg/dl for the control mean. After simultaneous pulse labeling with [3alpha-(3)H]campestanol intravenously and [23-(14)C]campestanol orally, the maximum percent absorption measured by the plasma dual-isotope ratio method as a single time point was 80% in the homozygote, 14.3% in the heterozygote, and 5.5 +/- 4.3% as the mean for three control subjects. Turnover (pool size) values estimated by mathematical analysis of the specific activity versus time [3alpha-(3)H]campestanol decay curves were as follows: 261 mg in the homozygote, 27.3 mg in the heterozygote, and 12.8 +/- 7.6 mg in the three control subjects (homogygote vs. controls, P < 0.001). The calculated production rate (mg/24 h) equivalent to actual absorption in the presence of dietary sterols and stanols was 0.67 mg/day or 31% of intake in the homozygote, 2.1 mg/day or 0.3% of intake in the heterozygote, and 0.7 +/- 0.3 mg/day or 0.1% of intake in the three control subjects. However, the excretion constant from pool A (K(A)) was prolonged markedly in the homozygote, but was 100 times more rapid in the heterozygote and three control subjects.Thus, campestanol, like other noncholesterol sterols, is hyperabsorbed and retained in sitosterolemic homozygotes. However, campestanol absorption was only slightly increased in the sitosterolemic heterozygote and removal was as rapid as in control subjects.
Two sons of a previously reported Ghanaian homozygote for the hereditary persistence of fetal hemoglobin (HPFH) (Ringelhann et al., 1970) also are HPFH homozygotes. In addition, another unrelated adult Ghanaian homozygote has been detected. All of these Ghanaian homozygotes as well as three American Black HPFH homozygotes have the G gamma A gamma type of HPFH with a G gamma to A gamma ratio of about 3:2, in contrast to an Asiatic Indian homozygote who has the G gamma type. Globin chain synthesis in HPFH homozygotes is unbalanced, with a gamma/alpha ratio of 0.6 or less, whereas it is balanced in heterozygotes according to most reports.
More than 90% of patients with type III hyperlipoproteinemia are homozygous carriers of the apolipoprotein (apo) E*2 allele. The great majority of these apoE2(Arg158-->Cys) homozygotes in the general population, however, are normolipidemic. Apparently, expression of the hyperlipidemic state requires additional genetic and/or environmental factors, suggesting a multifactorial etiology. To elucidate these additional risk factors, we analyzed normolipidemic and hyperlipidemic apoE2 homozygotes. Hyperinsulinemia was observed in 27 of 49 apoE2 homozygotes and associated with elevated lipid levels: hyperinsulinemic apoE2 homozygotes had type III hyperlipoproteinemia 6 times more often than apoE2 homozygotes with normal insulin levels (odds ratio 6.2, P=0.02). We screened the normolipidemic and hyperlipidemic apoE2 homozygotes for common variants in candidate genes involved in lipolysis-the APOA1-C3-A4 gene cluster, lipoprotein lipase, and hepatic lipase-and analyzed for associations with the expression of hyperlipidemia. In the hyperinsulinemic group, the 7 carriers of the SstI polymorphism (S2) in the APOC3 gene displayed severely elevated VLDL cholesterol (P(insulin by SstI)<0.001) and VLDL triglyceride (P(insulin by SstI)<0.01) and low levels of HDL (P(insulin by SstI)<0.02). In the normoinsulinemic group, no such relation of the SstI polymorphism with hyperlipidemia was observed. These data provide the first evidence for a combined effect of hyperinsulinemia and the SstI polymorphism on the expression of hyperlipidemia in apoE2 homozygotes.
In 2002, we reinvestigated a large synpolydactyly kindred first described in 1995. It was found to have expanded with an increase in number of homozygous offspring. These homozygotes had severe hypoplasia, with synpolydactyly of their hands and feet. We present the clinical, genetic, and surgical findings of this deformity and the histologic findings of the removed bones of the heterozygous and homozygous members. There were 125 affected individuals (113 heterozygotes and 12 homozygotes) of 245 members of the past five generations. We identified seven marriages in which both spouses were affected. Twelve offspring from these marriages had homozygote genetic patterns, hypoplastic synpolydactyly of the hands, and a distinctive foot deformity, with a prominent great toe and syndactylized hypoplastic minor toes. From clinical and surgical perspectives, their hand and foot deformities were different from those of their parents. We surgically treated both feet of four individuals with this deformity, which we called "homozygote foot synpolydactyly." Clinically, the deformity consisted of a supinated prominent great toe, hypoplastic and severely synpolydactylized minor toes, and secondary problems. Radiographically, the bones were underdeveloped, unshaped, and largely fused. Abundant cartilage covering the bones was observed surgically and histologically. Genetically, analysis of HOXD13 identified a 27-base pair duplication with a homozygote pattern. The foot deformity of the homozygotes was so distinctive and complicated that it should be considered a separate foot synpolydactyly type--homozygote foot synpolydactyly.
From January 1985 to January 1990, measurements of acid alpha-D-glucosidase activity in amniocytes or chorionic villus samplings were done for 24 pregnant mothers who were carriers of Pompe's disease. 6 women had two subsequent pregnancies. Amniotic fluid was obtained by transabdominal amniocentesis performed on 10 of them, while chorionic villus samplings were obtained in the other 20. The results showed that 7 (23.3%) cases were homozygotes, 16 (53.4%) cases were heterozygotes, and 7 (23.3%) cases were normal. Pregnancies were terminated in the homozygotic group. Final diagnosis was confirmed by either skin fibroblast culture or clinical course. However, we found that there was overlap in the acid alpha-D-glucosidase activity of amniocytes between homozygotes and heterozygotes due to residual activity of neutral alpha-D-glucosidase. In an attempt to identify heterozygotes for Pompe's disease, we established an enzyme inhibitory assay using monoclonal antibody (mAb) against acid alpha-D-glucosidase. Comparing the differences in alpha-D-glucosidase activity before and after mAb treatment the homozygotes were significantly lower than heterozygotes (P less than 0.001). There was no more overlap in the difference of acid alpha-D-glucosidase activity before and after mAb treatment between heterozygotes and homozygotes in amniocytes. This modified enzyme inhibitory assay should facilitate homozygote detection. Comparing acid alpha-D-glucosidase activity between CVS and amniocytes, the enzyme activity in CVS is about 5 times higher than in amniocytes. There was no overlap in the acid alpha-D-glucosidase activity between homozygotes and heterozygotes. Therefore, CVS is better than amniocentesis in the prenatal diagnosis of Pompe's disease.
BACKGROUND & AIMS: Typical hemochromatosis patients are homozygous for the C282Y mutation of the HFE gene. However, approximately 50% of women and 20% of men do not have an increase in serum ferritin level. This study assessed factors, genetic and otherwise, that may modify biochemical expression in C282Y homozygotes. METHODS: Hemochromatosis families that each had at least 2 untreated C282Y homozygotes were included. Nonexpressors were defined as having a ferritin level less than 300 microg/L for a male and a ferritin level less than 200 microg/L for a female. A multivariate linear stepwise regression analysis was performed to assess the contribution of sex, age, and the presence of a nonexpressor in the family on serum ferritin level. Heritability calculations were performed using variance component analysis. RESULTS: Fifty-three pedigrees consisting of 148 C282Y homozygotes (92 males, 56 females) were identified. Twenty-nine homozygotes were nonexpressors (19.6%), of which 11 of 29 were male (37.9%) (P=.0054). Based on multivariate analysis, highly significant associations with increased ferritin levels in C282Y homozygotes were male sex (P=.00005), increasing age (P=.009), and absence of a nonexpressor in the family (P=.01). Variance component modeling using age, sex, and C282Y genotype as covariates in 39 pedigrees (n=296) showed a residual heritability for serum ferritin of .35+/-.10 (P<.001). CONCLUSIONS: These findings suggest that male sex is the major clinical factor associated with an increased serum ferritin level in hemochromatosis. In addition, these results support the hypothesis that other genes contribute to the variance in serum ferritin concentration among C282Y homozygotes.
Marrow aspirates from heterozygotes and homozygotes for haemoglobin E (HbE) have been studied by electron microscopy and by the technique of combined Feulgen microspectrophotometry and 3H-thymidine autoradiography. The erythropoietic cells of heterozygotes did not contain any precipitated globin chains and the proliferating erythroblasts of such individuals showed no abnormality in their distribution in the different stages of interphase. By contrast, 0-1.5% of late erythroblast profiles and 3.1-12.8% of marrow reticulocyte profiles of homozygotes contained intracellular inclusions resembling precipitated alpha-chains. Although precipitated globin chains were not seen in the early polychromatic erythroblasts of homozygotes, the number of these cells in the G2 phase relative to that in the S phase was increased. These data indicate that there is probably little or no imbalance of globin chain synthesis in heterozygotes, a substantial degree of imbalance in homozygotes, and a disturbance of erythroblast proliferation in homozygotes which cannot be attributed to the deleterious effects of detectable intracellular alpha-chain precipitates. The electron microscope and cell cycle distribution data in the homozygotes for HbE were similar to those in two heterozygotes for beta thalassaemia.
Mutans streptococci (MS) and lactobacillus (LB) counts (CRT Bacteria chair-side test) were compared and correlated with the respective caries experience (DMF) of cystic fibrosis (CF) homozygotes (n = 20), CF heterozygotes (n = 20) and healthy controls (n = 20). Each group of subjects was divided into two equal age groups: group A <20 years and group B >20 years. No significant differences were found regarding DMF between the three groups. CF heterozygotes had a significantly higher DMF-S than CF homozygotes (p = 0.040). This was also found in age group B (p<0.02), where it also counted for DMF-T (p<0.01). When in age group B, CF heterozygotes and controls were combined as one group, it was found that they had a significantly higher DMF-T (p = 0.031) and DMF-S (p = 0.008) than CF homozygotes. No significant differences in LB counts between the three groups were observed. CF homozygotes and those in age group A had significantly (p = 0.018 and p = 0.015) more low MS counts. LB and MS counts were positive and significantly correlated with DMF-T/-S in CF homozygotes and in the combined group of CF heterozygotes with controls (p< or = 0.05 and < or = 0.001). No correlations between bacterial counts and DMF were observed in CF heterozygotes. It can be concluded that despite the fact that CF homozygotes behave as high caries risk individuals, they did not have significantly more dental decay. More research is required in order to explore salivary, dietary and medication influences.
Female common shrews in their first pregnancy were collected near Oxford (UK) from the hybrid zone between the Oxford and Hermitage races. These races differ by Robertsonian chromosomal rearrangements and both Robertsonian heterozygotes and homozygotes are found in the zone. The three homozygotes examined in this study had significantly more oocytes than the six heterozygotes. Among the heterozygotes, the number of oocytes tended to be lower in more severely heterozygous individuals; one double heterozygote was particularly depleted. Although there were, on average, 41% fewer primordial follicles in the ovaries of the heterozygotes than those of the homozygotes, there was no significant difference in the numbers of growing follicles between the karyotypic classes. These data suggest that Robertsonian heterozygotes may have a shorter reproductive lifespan than do homozygotes, but the numbers of follicles being recruited for ovulation at a particular instance during the fertile period does not appear to differ between homozygotes and heterozygotes. Morphological differences between the follicles of homozygotes and heterozygotes were not detected. Only 0.12% of healthy growing follicles were biovular.
Selection for an increased frequency of mutant semilethal allele Adh1-S of the gene for alcohol dehydrogenase (ADH) was conducted in inbred families of sugar beet. Starting from the fourth generation, viable plants of mutant Adh1-SS homozygotes appeared. In the sixth generation of selection, the combinative ability of mutant homozygotes SS, normal homozygotes FF, and heterozygotes FS was estimated. The hybrids of mutant homozygotes outperformed the hybrids of normal homozygotes in all parameters examined (germinating capacity of seeds, length and weight of 1-week shoots, chlorophyll content in leaves, and root weight). The hybrids of heterozygotes had intermediate values of the parameters. The results obtained are discussed with regard to the mechanisms underlying the recovery of viability of mutant homozygotes and the formation of a compensating gene complex (CGC).
BACKGROUND: Familial ligand-defective apolipoprotein B 100 (FDB) is an autosomal inherited disease due to mutations on apo B 100, clinically indistinguishable from familial hypercholesterolemia (FH). We described the first Spanish homozygote for FDB. METHODS: We have screened R3500Q mutation of apo B gene (PCR-SSCP analysis) in a large family with FDB and have identified the first Spanish homozygote for FDB. RESULTS: The homozygote is a 58 year-old man with coronary heart disease, no presence of xanthomata and with total cholesterol and LDL cholesterol plasma levels of 415 and 352 mg/dl. The response to statins and resins was up to 42% for total cholesterol and 51% for LDLc plasma values. The LDL receptor activity was normal in the FDB homozygote. CONCLUSIONS: We have identified and characterised the first Spanish homozygote for FDB (R3500Q mutation). Our data indicate a moderate lipoprotein phenotype in FDB homozygote, different as expected comparing to homozygous FH.
Although hereditary hemochromatosis is an autosomal recessive disease, most homozygotes are concerned with the genetic implications for their children. The optimal age for testing children and the cost implications of screening their children have not been clearly established. A clinical database consisting of 255 children from families with at least one homozygote is used to assess the prevalence of homozygotes among children of homozygous parents and to review the biochemical abnormalities and life-threatening symptoms in these young adults. Decision analysis is used to estimate the cost and utility of screening children of a homozygous parent. Eleven homozygotes were discovered among children of homozygotes. Only one male had a life-threatening event, cirrhosis. Decision analysis estimated cost saving of $12 per child screened ($ net present value) and a saving of 10 quality-adjusted days per child screened at age 10 years compared with not screening. If screening began at age 20 years, there is a cost saving of $65 per child screened. Sensitivity analysis showed that the major factors influencing cost savings were the cost of venesections, sensitivity and specificity of the screening tests, and prevalence of disease. Because the prevalence of hemochromatosis is higher in children of homozygotes than in the general population, screening with transferrin saturation and ferritin as early as age 10 years is recommended. Savings are augmented if the cost per venesection is eliminated by allowing hemochromatosis patients to become voluntary blood donors.
OBJECTIVE: Sitosterolemia is a genetic disorder characterized by an increased plasma plant sterol concentration due to enhanced sterol absorption coupled with reduced steroid excretion. The purpose of the present investigation was two-fold; first to assess the effects of a "basal" low sitosterol metabolic diet on plasma sterols and sterol balance, and, secondly, to quantify the relative influence of graduated increase in dietary sitosterol intake on a metabolic diet in a sitosterolemic homozygote, obligate heterozygote, and controls. METHODS: Patients were studied under strict metabolic conditions and fed a "basal" 30% fat, low-sitosterol (33 mg per 2000 kcal) diet. The level of dietary sitosterol was increased by addition of oils and resulted in final dietary sitosterol intakes of 1.8 mg/kg, 2.6 mg/kg and 3.5 mg/kg/day intakes of dietary sitosterol in the homozygote. These sitosterol dosages were selected based on sitosterol intakes equivalent to 2.6 mg/kg/day in the average American diet. Plasma cholesterol, sitosterol, and apolipoprotein A were measured, and stool collections assayed for sterol balance. RESULTS: Fecal sterol excretion and cholesterol synthesis were depressed markedly by 50% in the homozygote compared to the heterozygous parent, whereas plasma sitosterol levels were increased over 50-fold. When the sitosterol content of the diet was increased three-fold and dietary cholesterol was maintained in the homozygous and hypercholesterolemic control, plasma levels did not increase in the homozygote. Plasma cholesterol and sitosterol levels were unaffected in the hypercholesterolemic control. CONCLUSIONS: Plasma sterol levels remained elevated with the dietary sitosterol changes in the sitosterolemic homozygote. These findings were associated with a low fecal sterol excretion rate and depressed endogenous cholesterol synthesis. In this sitosterolemic patient, a very low sitosterol diet to curtail sterol input was of minimal therapeutic benefit. These results have important implications regarding the selection of therapy for this patient under these experimental conditions, but cannot be generalized to other homozygotes.