Male Homozygotes Research Articles

Ultrastructural and morphometrical analyses of Leydig and Sertoli cells in the testes of rats with hereditary polydactylism.

Rats of the polydactylous (PD) strain carry an autosomal recessive gene pd that causes polydactylism in homozygotes (pd/pd). Male homozygotes are sterile owing to an abnormality of spermatogenesis. In the present study, Leydig and Sertoli cells of 12-week-old pd/pd male rats were examined for ultrastructural alterations in an attempt to clarify the cause of the abnormal spermatogenesis. The relative volumes of the organelles were also determined with morphometry. Phenotypically normal pd/+ males served as controls. No morphological or morphometrical abnormalities were noted in the Leydig cells. However, two different types of Sertoli cell were evident: light cells and dark cells. The incidence of the dark Sertoli cells in pd/pd males was high (27%) compared with that in pd/+ males (6%). These dark cells contained quantities of lipid droplets in the cytoplasm and exhibited a significant increase in the relative volume of lipid droplets compared with the value for the light cells. The nuclei of the dark Sertoli cells were irregular in shape and were invaginated. These results suggest that dark Sertoli cells may have lower lipid metabolism, and in pd/pd males, the high number of these dark Sertoli cells may be related to abnormal spermatogenesis.

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Sexually dimorphic sterility phenotypes in Hoxa10-deficient mice.

The Abdominal B (AbdB) genes constitute a distinct subfamily of homeobox genes that exhibit posterior domains of expression, including the genital imaginal disc in Drosophila and the developing urogenital system in vertebrates. We have mutated the AbdB gene Hoxa10 in mice. We report here that homozygotes are fully viable and show an anterior homeotic transformation of lumbar vertebrae. All male homozygotes manifest bilateral cryptorchidism resulting in severe defects in spermatogenesis and increasing sterility with age. Female homozygotes ovulate normally, but about 80% are sterile because of death of embryos between days 2.5 and 3.5 post coitum. This coincides spatially and temporally with expression of maternal Hoxa10 in distal oviductal and uterine epithelium. These results indicate a role for AbdB Hox genes in male and female fertility and suggest that maternal Hoxa10 is required to regulate the expression of a factor that affects the viability of preimplantation embryos.

高ビリルビン尿症ラット (EHBR, Eizai Hyperbilirubinuria Rat) の確立とその病態について

A new animal model for jaundice, a hyperbilirubinemic rat mutant (EHBR, Eizai hyperbilirubinuria rat), was established from Sprague-Dawley rats. Hyperbilirubinemia was inherited as an autosomal recessive trait. The gene manifesting jaundice was named "hyb". Homozygotes developed jaundice immediately after birth, and a high bilirubin concentration was detected in plasma and urine. The plasma bilirubin levels were high in the neonatal period, but they decreased from 6 to 10 weeks old. In male homozygotes, plasma bilirubin levels increased rapidly until about 40 weeks, and decreased thereafter. Female homozygotes showed slightly high plasma bilirubin levels until 56 weeks, then increased rapidly thereafter. At 72 weeks, the plasma bilirubin level of females was comparable to that of males. About 80 percent of the plasma bilirubin was conjugated. Plasma biochemistry demonstrated the increase of total cholesterol and total bile acid in the homozygotes. Histopathologically, the homozygote was characterized by brown pigment in the hepatocytes, and glomerular lesions with mesangial expansion. From these findings it was considered that EHBR might be a useful animal model for studying constitutional conjugated hyperbilirubinemia and bilirubin metabolism.

Genetic Analysis and Histology of Hypoplastic Kidneys in the Male Hypogonadic Mutant (hgn/hgn) Rat

Bilateral hypoplastic kidneys have been found to associate with the male hypogonadism rat (hgn/hgn). The hypoplastic kidney was persistent to the male homozygote for hgn and it was also seen in some females with unknown genotype. The affected kidney was apparently smaller in size than phenotypically normal one. When females with hypoplastic kidney were mated to proven heterozygous males for hypogonadism (hgn/+), the ratio of the affected testis to phenotypically normal one was 32: 20 in the Fl generation. This segregation ratio did not deviate siginificantly from the 1: 1 ratio expected from the hypothesis that the genotype of females with hypoplastic kidney in parent generation for hypogonadism would consist of hgn/hgn alone. The ratio expected from the other hypotheses was denied statistically. The ratio of the affected kidney to phenotypically normal one in both sexs of the Fi was 53: 50, fitting to 1: 1 hypothesis for a single autosomal recessive trait. There was neither a case showing the phenotypically normal kidney with the affected testis, nor the hypoplastic kidney with the phenotypically normal testis. The results suggest that the gene responsible for the hypoplastic kidney and the gene for hypogonadism would be identical or both genes reside in the close vicinity in a chromosome. The results also suggest that the homozygotes for hgn can be selected by the presence of hypoplastic kidney.

Effect of Vitamin C Depletion on Serum Cholesterol and Lipoprotein Levels in ODS (od/od) Rats Unable to Synthesize Ascorbic Acid

The effect of ascorbic acid deficiency on serum and liver cholesterol, phospholipid and triglyceride levels, serum lipoprotein levels and serum lipoprotein cholesterol levels were examined in male rats with a hereditary defect in ascorbic acid synthesis (ODS rats). Male homozygotes (od/od) and male rats of their parent strain (+/+) were each divided into four treatment groups and were fed vitamin C-deficient or vitamin C-replete diets containing either 0 or 0.5% cholesterol. During the 3-wk feeding-period the ODS (od/od) rats fed the vitamin C-deficient diet gradually decreased food intake, resulting in a lower body weight than that of od/od rats given ascorbic acid. The serum cholesterol level was significantly higher in the vitamin C-deficient od/od rats fed the cholesterol diet, and it tended to be higher in those fed the control (0% cholesterol) diet, whereas the liver lipid levels remained unchanged relative to those in od/od rats fed the vitamin C-replete diet. The serum very low density lipoprotein and high density lipoprotein (HDL) cholesterol levels were lower in od/od rats fed the vitamin C-deficient diet without cholesterol, but intermediate density lipoprotein and low density lipoprotein cholesterol levels were markedly higher in the vitamin C-deficient od/od rats than in od/od rats given ascorbic acid, regardless of dietary cholesterol level. The ratio of HDL2 cholesterol to HDL3 cholesterol was also higher in the vitamin C-deficient od/od rats. The parent strain of the od/od rats (+/+) showed no change due to vitamin C deficiency. These results suggest that vitamin C deficiency delays low density lipoprotein metabolism and produces hypercholesterolemia in male od/od rats.

Analysis of the hotfoot ( ho) locus by creation of an insertional mutation in a transgenic mouse

Hotfoot ( ho) mutation is a recessive trait in mice, characterized by motor disorder and male sterility, that maps to chromosome 6. We have identified a transgenic mouse pedigree with a similar trait. Using genetic and molecular approaches, we have demonstrated that the foreign DNA element is located in or near the ho locus. This new allele, designated ho Jwg and presumably created by insertional mutagenesis, should make it possible to clone the ho gene. Male infertility in ho Jwg male homozygotes was determined to be due to inability of sperm to penetrate the zona pellucida. This was demonstrated by rescuing mutant males by a new technique of gamete micromanipulation, zona pellucida drilling. These findings show that zona drilling is useful both for analysis and preservation of animals with reduced male fertility.

Twenty-four hour variation of transferrin saturation in treated and untreated haemochromatosis homozygotes.

We studied 43 haemochromatosis homozygotes and seven normal individuals to test the hypothesis that there is an almost continuous relative deficiency of apotransferrin in treated and untreated homozygotes. Transferrin saturation was measured at 2-h intervals for 24 h while all subjects ate their usual diet. Subjects with haemochromatosis were separated into four groups based on sex and whether or not they had been iron-depleted. Nineteen treated and 11 untreated male homozygotes had mean transferrin saturation values of 70 and 81%, respectively. Five treated and eight untreated female homozygotes had mean transferrin saturation values of 71 and 69%. Normal subjects had mean transferrin saturation values of 29% (3 males) and 21% (4 females). These data demonstrate continuously high transferrin saturation values, greater than 69% in most treated and untreated male and female homozygotes, resulting in hepatic iron accumulation of non-transferrin-bound iron from the portal circulation.

GENETIC VARIATION AND JUVENILE SURVIVAL IN RED DEER.

The survival of red deer (Cervus elaphus L.) calves to two years of age was examined in relation to electrophoretic variation in a population on the Scottish island of Rhum. Survival was analyzed using logistic analysis in which the "phenotypic" factors birth weight, birth date, subdivision of the study area, cohort, and sex, which affect the probability of a calf's survival, were taken into account. All three polymorphic loci examined, Mpi, Idh-2, and Trf (each with two detected alleles) are significantly associated with juvenile survival. At Mpi, there is selection against one allele, f (or an allele at a linked locus), and there are indications that this effect is stronger in females than males. For Idh-2, overall, the heterozygote class survives better than the two homozygotes, which survive equally well. However, again there is a difference between the sexes; female heterozygotes survive much better than homozygotes, whereas male homozygotes survive better than heterozygotes, and the difference in survival is smaller. Furthermore, there is an interaction involving Mpi, Idh-2, and survival in which Mpif carriers that are also Idh-2 homozygotes survive very badly compared with other Mpi-Idh-2 combinations, which all survive equally well. For Trf, the heterozygote class survives best, and there is also a difference in survival between the two homozygote classes. Genotype frequencies in the adult population are consistent with the results for calf survival, in that the Mpif frequency is lower in succeeding cohorts of surviving adults, whereas no significant gene frequency change is apparent for Idh-2 or Trf.

The effect of iron fortification of the diet on clinical iron overload in the general population.

The gene coding for idiopathic hemochromatosis is prevalent in Sweden, the country with the highest iron fortification of food (42%) in the world. We wanted to study if this highly iron-fortified diet had negative effects on the iron situation in carriers of the iron-loading genes. Iron stores averaged 6.7 grams in male homozygotes who were mainly identified through laboratory screening. It was 3.4 grams in female homozygotes. By HLA typing of family members of these homozygous probands, 39 additional homozygotes and 172 heterozygotes were detected. Serum ferritin averaged 620 micrograms/l in 20 male and 168 micrograms/l in 19 female homozygotes in the family screening. Storage iron as measured by serum ferritin concentration was slightly but significantly higher in male heterozygotes than controls (117 micrograms/l versus 87 micrograms/l, p less than 0.02). There was no further increase in serum ferritin concentration with age after 40 years. Heterozygotes showed no clinical signs of iron damage. These findings do not indicate that carriers of the iron-loading genes in Sweden have been adversely affected by the highly iron-fortified diet of the country.

An unusual cause of lymphoedema—confirmed by isotopic lymphangiography

We describe here a rare case of lymphoedema (Anderson-Fabry's disease) and its examination using isotopic lymphography. Anderson-Fabry's disease gives rise to various multisystem problems including lymphoedema which are all secondary to the deposition of glycosphingolipids in venous tissue. The prognosis particularly in homozygote males is poor.

Green pupa (gp), a male lethal in culex quinquefasciatus.

An autosomal recessive mutant, green pupa (gp), in Culex quinquefasciatus has been isolated. The homozygous (gp/gp) females are viable whereas male homozygotes do not develop beyond the pupal stage. The behavior of this mutant character in pedigree studies has been reported.

Juvenile ataxia--a new behavioral mutation in the deermouse.

An autosomal recessive behavioral mutation designated juvenile ataxia (ja) was first isolated from F2 progeny of four blonde (bl) Peromyscus maniculatus bairdi siblings. Juvenile ataxic homozygotes exhibit an ataxic gait without an associated tremor from 15 days postpartum. This ataxia continues but does not increase noticeably in severity until between 35 and 43 days of age. Thereafter, a rapid and dramatic improvement in the behavior pattern is seen, so that juvenile ataxic deermice over 45 days of age are phenotypically indistinguishable from wild type or heterozygotes of the same age. Female juvenile ataxic homozygotes rarely breed, while male homozygotes are fully fertile. Linkage tests between juvenile ataxia and blonde suggest that these two mutations are not allelic and are not tightly linked. Testing between juvenile ataxia and a previously described neurological mutant, boggler (bg), indicates that complementation between these two mutations is incomplete, and suggests that boggler and juvenile ataxic may represent allelic mutations.

Clinical and biochemical expression of the genetic abnormality in idiopathic hemochromatosis

The pattern of transmission of the predisposing alleles of idiopathic hemochromatosis was traced in 111 members of 12 pedigrees by typing for the A and B alleles of the HLA complex. The 12 probands were assigned the status of homozygotes. Other family members were grouped according to their HLA typing into one of three categories independent of their iron stores: homozygotes who shared two haplotypes with the proband; heterozygotes who shared one haplotype; and normals who lacked both haplotypes. Clinical manifestations of iron loading were prevalent in male homozygotes and absent in heterozygotes and normals. The results of tests of iron metabolism were compared with age- and sexmatched controls. Abnormalities in 12 probands and 6 discovered homozygotes were characterized by a significant increase in mean serum iron, a decrease in serum transferrin, an increase in both transferrin saturation, and serum ferritin. Similar but less marked abnormalities were found in 25% of 69 heterozygotes with the exception that mean serum ferritin was normal. In 24 normal family members a slight increase in mean serum iron and transferrin saturation was detected, but mean serum ferritin was normal. Radioiron absorption in relation to the respective serum ferritin concentration measured in selected subjects was markedly increased in 10/10 homozygotes, moderately increased in 5/14 heterozygotes and within the control range in 2/2 normals. In summary, phenotypic expression of hemochromatosis was characterized by increased serum iron, decreased transferrin, increased serum ferritin, and iron absorption relative to serum ferritin in both homozygous males and females, but a major degree or iron loading with clinical features was only prevalent in homozygous males. Partial biochemical expression of the disorder in some heterozygotes was associated with an increase in iron absorption and a minor degree of iron loading in the absence of clinical manifestations.

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 fluctuations 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.