Deficiency Alleles Research Articles

Alpha-1-antitrypsin allele PiS fails to show segregation distortion.

Recent reports suggest that despite negative selection pressure, the deficient alpha-1-antitrypsin allele, PiZ, is maintained in a state of balanced polymorphism through the action of segregation distortion in heterozygous males. Published family data suggest that the same mechanism may be operating on behalf of the partially deficient allele PiS. Back-cross and intercross data, involving more than 250 informative meioses for PiS are reported here. Segregation analysis fails to confirm the hypothesis that the PiS allele is preferentially transmitted.

Late-Onset 21-Hydroxylase Deficiency Is an Allelic Variant of Congenital Adrenal Hyperplasia Characterized by Attenuated Clinical Expression and Different HLA Haplotype Associations

Three families with late-onset 21-hydroxylase deficiency were studied. Homozygous females presented with symptoms of mild hyperandrogenism such as acne, hirsutism, oligomenorrhea and menometrorrhagia. A homozygous male was asymptomatic and had reached normal adult height. The diagnosis of 21-hydroxylase deficiency was based upon markedly elevated responses of plasma 17-hydroxyprogesterone during a short (30-min) ACTH infusion test. The propositi of two of the families were diagnosed despite long-standing glucocorticoid therapy and adrenal suppression by using a prolonged (48-hour) ACTH infusion. Heterozygotes of late-onset 21-hydroxylase deficiency had mildly elevated 17-hydroxy-progesterone responses to ACTH. Late-onset 21-hydroxylase deficiency was inherited as an autosomal recessive trait with close linkage to the histocompatibility leukocyte antigens. The B14 haplotype was present in all affected members. One affected female had a daughter with classic, salt-losing 21-hydroxylase deficiency. Mixed heterozygosity of this patient for a classic and a late-onset 21-hydroxylase deficiency allele may have caused the classic phenotype in her daughter (homozygote for 2 classic alleles).

HLA-linked genetic markers in Chinese and other Oriental populations.

The polymorphic variants of the HLA-linked genetic markers Bf, C2, C4 and GLO-I were studied in three mongoloid populations. Analysis of linkage dis-equilibrium between these markers and HLA-A, B, C and DR antigens was carried out on test results from 140 unrelated Chinese individuals. The phenotypes BfS and GLO-2 were found at significantly higher frequencies than in Caucasians. BfS was associated with B12 in Japanese but not in Chinese. A single individual with the rare Bf variant S1 was found. No C2 deficient individuals were observed. The C2C (common) allele occurred at a gene frequency of 0.949 and the more basic allele C2B at 0.039. The acidic variant, C2A, was observed at a frequency of 0.011 and appeared to be associated with BfF. Eighty-nine per cent of the Chinese were phenotypically C4FS. In contrast to Bf and C2, each of which is coded for by codominant alleles at a single genetic locus, C4 is coded for by two genes, C4F (Rodgers) and C4S (Chido). The C4F locus allele, C4F1 (extra fast), was strongly associated with HLA-B17, as has been found in other populations, but a new association of the C4S locus deficiency allele, C4so (Ch-), with B17 was also observed. All HLA-B17;C4so haplotypes were BfS position. As has been previously found in Caucasian populations, individuals of the C4F phenotype (i.e. genotypically FsoFso) were all found to be Chido negative. The frequencies of the various HLA-linked genetic markers, however, as much as the frequencies and associations of the HLA antigens themselves, distinguish these populations from other ethnic groups.

Congenital adrenal hyperplasia

Congenital adrenal hyperplasia (CAH) is a family of disorders produced by enzymatic deficiencies of adrenal steroidogenesis. Oversecretion of ACTH secondary to impairment of cortisol synthesis stimulates excessive synthesis of the precursors of the enzyme defect and accumulation of the products of those adrenal hormones whose synthesis is unimpaired by the enzyme deficiency. The most frequent enzyme deficiency is that of 21-hydroxylation. Deficiencies of the enzymes 11β-hydroxylase, 3β-hydroxysteroid dehydrogenase (3β-HSD), 17α-hydroxylase, and cholesterol desmolase has also been reported. Ambiguous genitalia presenting at birth is the most important clinical feature of CAH due to 21-hydroxylase and 11β-hydroxylase deficiencies in genetic females as a result of excessive secretion of adrenal androgens prenatally. In 3β-HSD, 17β-hydroxylase, and cholesterol desmotase deficiency, androgen synthesis is impaired and thus cirilization of the genitalia in genetic males is incomplete. Salt-wasting is associated with those forms of CAH with deficient mineralocorticoid production; in other forms, hypertension may result from accumulation of steroid precursors with salt-retaining properties. Defects of 18-hydroxylase, and 18- dehydrogenase cause a defect in atdosterone synthesis, while 17-hydroxysteroid reductase, and 17–20 lyase deficiencies cause androgen deficiency without interrupting cortisol synthesis. With respect to regulation and secretion, a recent concept is that the adrenal zona fasciculata and zona glomerulosa function as two separate glands: the fasciculata is primarily regulated by ACTII and the glomerulosa by the reninangiotensin system. It has been documented that in CAH due to the 11β-hydroxylase deficiency there is a defect in 11- and 18-hydroxylation in the fasciculata while the enzymatic activity of these enzymes in the glomerulosa is normal. The concept that the fasciculata and glomerulosa function as two separate glands has been applied to CAH due to 21-hydroxylase deficiency. A new hypothesis to explain the presence or absence of salt-wasting signs in CAH due to 21-hydroxylase deficiency is as follows: i) in both simple virilizers and saltwasters there is a fasciculata defect of 21-hydroxylation in both the 17-hydroxy and 17-desoxy pathways, and ii) in saltwasters there is a 21-hydroxylase defect in the glomerulosa as well, while in simple virilizers the glomerulosa is spared this defect. The ability of simple virilizers, but not saltwasters, to respond to renin-angiolensin stimulation with an increase in aldosterone secretion supports this hypothesis. Close genetic linkage between HLA and 21-hydroxylase deficiency has been recently demonstrated, and the 21-hydroxylase deficiency gene has been mapped in close proximity to the HLA-B genetic locus. HLA genotyping, in addition to hormonal testing, is useful for the detection of heterozygote carriers for 21-hydroxylase deficiency and prenatal diagnosis in families with an affected index case. Two non-classical, FILA-linked forms of 21-hydroxylase deficiency are described: the late onset form and the asymptomatic “cryptic” form. Hormonal standards are presented for genotyping 21-hydroxylase deficiency, demonstrating a spectrum in the degree of enzymatic deficiency ranging from a severe deficiency in the classical form to a milder deficiency in the late onset and cryptic disorders, to a still milder deficiency detectable only with ACTII stimulation in heterozygotes for all three forms. It is also proposed that the cryptic disorder represents a genetic compound of the classical and mild 21-hydroxylase deficiency alleles. Studies of genetic linkage disequilibrium suggest that some late onset patients may also be genetic compounds, possessing both a mild and a classical 21-hydroxylase deficiency allele. A microfiller paper method for measuring 17-OHP for the neonatal diagnosis of 21-hydroxylase deficiency is described. The results of a pilot newborn screening program for CAH using the 17-OHP microfilter paper method demonstrates that screening for this disorder is feasible. Further 21-hydroxylase deficiency occurs with sufficient frequency to warrant screening. Measurement of 17-OHP and Δ4 in amniotic fluid make possible the prenatal diagnosis of 21-hydroxylase deficiency. The fundamental aim of therapy in CAH is to provide replacement of the deficient hormones. Glucocorticoid administration both replaces the deficient cortisol and suppresses ACTH production, resulting in a decrease in adrenal androgens which produce virilization and ultimate short stature. Mineralocortocoid supplement is required in the salt-wasting disorders. Mineralocorlicoid administration is also recommended for patients with elevated plasma renin activity but no evident symptoms of salt-wasting, to improve the control of androgen oversecretion. Recognition of this disorder is important in the sex assignment of newborns with ambiguous genitalia.

Quantitative variations of red-cell cytochrome b5 reductase (NADH-methemoglobin-reductase) in the Algerian population: evidence for defective alleles.

A striking proportion of Algerian subjects was reported among patients with congenital recessive methemoglobinemia due to cytochrome b5 reductase deficiency (Kaplan et al. 1979). A population survey was carried out in red blood cells from 1000 Algerian subjects. In 16 subjects, the cytochrome b2 reductase activity was diminished by 50%. Family studies indicated the presence of a defective allele with an overall gene frequency of 0.008. Immunologically cross-reacting material was found in red cells with low cytochrome b5 reductase activity. Leukocytes exhibited normal levels of enzyme in some families and low levels in others suggesting that at least two different deficient alleles at the DIA1 locus were present in the Algerian population. A higher prevalence of the deficient allele(s) was found in subjects of Kabyle origin.

Genetic polymorphism of serum complement components in the chimpanzee

Significant polymorphism of serum complement components Bf, C2, C3, C6, and C8 in the chimpanzee has been demonstrated. The data are consistent with the hypothesis that C2 and Bf are closely linked to ChLA and argue against close linkage of ChLA to C3 or to C8, as in man. In addition, a blank allele for C6 and C6 deficiency was detected in several chimps.

Preferential Transmission of the Z Deficient Allele of α 1 -Antitrypsin

The transmission of the Z deficient allele of alpha 1-antitrypsin was studied in 23 families, each with a single parent heterozygous for this allele. When the mother carried the Z allele, the distribution of phenotypes in the children did not differ significantly from the expected frequency. In contrast, when the father was the carrier, a significant increase of heterozygous phenotypes was observed in the children. This observation suggests that a selective advantage is associated with the expression of the Z allele in male gametes.

The Genetics of Dopa Decarboxylase and a-Methyl Dopa Sensitivity inDrosophila melanogaster

Dopa decarboxylase (DDC) in the Diptera is an enzyme involved in sclerotinization of the cuticle in the epidermis and the production of neurogenic amines in the central nervous system. Its appearance in the epidermis at pupariation is induced by the molting hormone ecdysone. The dietary administration of the analog inhibitor α-methyl dopa (a MD) was used to isolate resistant and hypersensitive mutants. Two of three dominant resistant strains isolated increase DDC activity 35-70%. For both the increase is due to mutations between rdo (53) and pr (54.5) on the left arm of the 2nd chromosome (2L). The very highly resistant strain which does not affect DDC in any way is located at 54.0 on 2L. Twelve dominant, l(2) amdH —α MD hypersensitive alleles located immediately to the right of hk (53.9) on 2L have been recovered. All are recessive lethals and exhibit some intracistronic complementation, and none of them, not even heteroallelic heterozygotes, affect DDC in any way. The.recovery and analysis of 16 overlapping deficiencies permitted the localization of a DDC dosage effect to bands 37B10-C7 on 2L; a region which includes the l(2) amd locus. Subsequently eight DDC deficient lethal alleles were recovered in this eleven band region which as heterozygotes reduce activities to 28–53 % of controls. Some heteroallelic heterozygotes exhibit intracistronic complementation; most with viabilities 5% and with a mutant phenotype probably derived from inadequately sclerotinized cuticle. These Ddc alleles are within 0.004 Map Units to the right of l(2) amd . None as Ddc/CyO heterozygotes are sensitive to α-MD, and complementation occurs between the Ddc alleles and the l(2)amd alleles both on the basis of viability and DDC activity. Although the protein product mutated by the l(2) amd alleles has not yet been identified, it seems likely that the two groups of mutants are functionally related. Finally, the Ddc structural mutants reduce DDC activity in the central nervous system as well as the epidermis.

Alpha-1-antitrypsin bodies in the liver.

The cytoplasmic bodies in hepatocytes thought to indicate possession of the Z allele for alpha 1-antitrypsin deficiency were found in necropsy in 10 of 64 adults with cirrhosis, four of nine with hepatic fibrosis, and four of 15 with hepatocellular carcinoma. They were also found in six of 76 adults with severe panacinar emphysema, and in four of a control series of 110 adults with neither emphysema nor liver disease. The association of the bodies with each of the three liver diseases was statistically significant, but the association of the bodies with emphysema was not. It is considered probable that heterozygous (PiMZ) alpha 1-antitrypsin deficiency is associated with an increased incidence of cirrhosis, hepatic fibrosis, and hepatocellular carcinoma.

A chlorophyll-deficiency factor in the natural populations ofTephrosia purpurea (L.) Pers

The selection coefficient for the deficiency allele and the proportion of the two alleles in the populations are estimated. The apparent vegetative and reproductive vigour in the populations with the factor is attributed to the combined effect of low population density caused by the death of the double recessives and the higher selective value of the heterozygotes in these populations. A model of balanced polymorphism involving a recessive lethal is suggested to explain the results.

The genetics of dopa decarboxylase in Drosophila melanogaster. II. Isolation and characterization of dopa-decarboxylase-deficient mutants and their relationship to the alpha-methyl-dopa-hypersensitive mutants.

Of 84 lethals isolated over the dopa decarboxylase (DDC) deficiency Df(2L)50, 8 have been identified as DDC-deficient alleles on the basis of their effect on DDC activity when heterozygous over the Cgamma-O balancer chromosome with activities ranging from 28% to 53% of controls. Some of the Ddc-deficient alleles exhibit intracistronic complementation. Most of the complementing pairs of alleles are much reduced in viability, e.g. less than 5% of expected, and express a common syndrome of mutant phenes which can reasonably be inferred to derive from inadequately sclerotinized cuticle. Individuals heterozygous for the noncomplementing allele, Ddcn7, over the 12-band DDC deficiency, Df (2L)130, die at the end of embryogenesis as unhatched larvae with unpigmented mouth parts. The Ddc alleles and the l(2) amd alpha-methyl dopa (alphaMD) hypersensitive alleles are both located within the 11 band region 37B10-C7. The l(2) and locus is immediately to the right of hk(2-53.6). Ddc has been mapped within 0.004 Map Units to the right of l(2) and with a maximum estimated recombination frequency of 0.01%. None of the Ddc/CgammaOstrains are sensitive to the dietary administration of alpha-methyl dopa (alphaMD), and complementation occurs between the Ddc deficient alleles and the l(2) amd alleles both on the basis of viability and DDC activity. No effect on DDC by the amd alleles has been found to date. Even in the complementing heterozygote, amdH1/amdH89, the level of activity, thermostability, and in vitro alphaMD inhibition of DDC remains unaffected. Although no biochemical phene has yet been established for the alphaMD hypersensitive amd alleles, it seems likely that the two groups of mutants are functionally related.

The frequency of isoniazid acetylase enzyme deficiency among Egyptians.

AbstractThe frequency of isoniazid slow inactivators is very high among Eqyptians, 82% have more than 0.91 γ/ml of free INH in serum specimens obtained six hours after a single dose of 10 mgm/kgm. The incidence of the allele for INH acetylase enzyme deficiency is estimated at 0.9059 and that of the heterozygous carrier of this allele at 0.1705.

Congenital Factor VII Deficiency with Normal Stuart Activity: Clinical, Genetic and Experimental Observations

Abstract The case of a four year old white girl with a bleeding tendency characterized by the spontaneous occurrence of petechiae, ecchymoses and hemarthroses is presented. Laboratory studies indicate a deficiency of factor VII, with normal levels of all other clotting components, and a vascular deficiency possibly related to frequent upper respiratory infection. Serum from the patient and from four close relatives having reduced levels of factor VII is shown to correct the abnormal thromboplastin generation of Stuart factor-deficient serum. The rate of conversion of prothrombin into thrombin is markedly delayed in the patient’s plasma but essentially normal in that of other family members. The patient’s prothrombin conversion is corrected by the addition of normal or Stuart-deficient plasma. The partial thromboplastin time of the patient is somewhat prolonged. It is concluded that factor VII deficiency is inherited in this family as an incompletely recessive autosomal characteristic. The penetrance of the deficiency allele in the heterozygous individual appears to be variable. Analyses of the distributions of clotting factor levels in the family and in samples from the normal population indicate that an individual may vary greatly in his clotting factor levels, the average variation being nearly as great as the variation among individuals. The magnitude of the variation among siblings suggests that the penetrance of the factor VII deficiency allele is affected by extrinsic factors and that the observed population variation does not result from the occurrence of multiple alleles. It is suggested that sex may be a factor determining clotting factor levels. The bleeding of the patient is controlled by transfusion of plasma and by injection of a plasma preparation called ACC-76 (Behringwerke, Germany), the latter followed by a transient elevation of blood factor VII.