Heterozygotes For Deficiency Research Articles

Reference Values for Quantitative Testing of G6PD Deficiency in Newborns from the Republic of North Macedonia

Glucose-6-phosphate dehydrogenase is a key regulatory enzyme in the pentose-phosphate cycle that participates in the formation of reduced equivalents to maintain the cellular redox status. The G6PD enzyme activity is crucial in protecting cells from oxidative stress. Deficit of the glucose-6-phosphate dehydrogenase (G6PD) has been recognized as the most common inherited enzymopathy worldwide. In the Republic of North Macedonia (RNM), the deficit of glucose-6-phosphate dehydrogenase has been infrequently investigated. Moreover, no reports exist on quantitative testing of G6PD in newborns from the RNM. SCOPE: The aim of our study was to determine the reference values for the level of G6PD in erythrocytes of newborns from the Republic of North Macedonia. For this purpose, eighty-two healthy newborns were selected and tested for G6PD by the quantitative spectrophotometric method. RESULTS: The mean ± SD of the G6PD quantitative value in the examined group was 229.12 ± 24.2 mU/109Er ranging from a minimum of 191.7 to a maximum of 288, and a median of 228.0 mU/109Er, values that were lower than the preset reference values of the diagnostic test in use. CONCLUSION: We speculated that by establishing a specific reference value (range) for the target population and for the appropriate diagnostic test, we would gain increased sensitivity of the test. This would help optimize detection of G6PD deficient newborns, mild-variant hemizygotes and female heterozygotes for the deficiency.

Reassessment of predictive values of ACTH-stimulated serum 21-deoxycortisol and 17-hydroxyprogesterone to identify CYP21A2 heterozygote carriers and nonclassic subjects.

Heterozygotes (HZs) for 21-hydroxylase deficiency (21OHD) are highly prevalent, ranging from 1:60 to 1:11 for classic and nonclassic (NC) forms, respectively. Detection of HZ and asymptomatic NC by CYP21A2 genotyping is valuable for genetic counselling, but costly, complexand narrowly available. Adrenocorticotropic hormone (ACTH)-stimulated serum 17-hydroxyprogesterone (17P) and 21-deoxycortisol (21DF) discriminate 21OHD phenotypes effectively, notably if measured simultaneously by liquid chromatography-tandem mass spectrometry (LC-MS/MS). This study was performed to reassess former LC-MS/MS-defined post-ACTH 21DF, 17Pand cortisol (F) cutoffs in family members at risk for 21OHD. Prospective study in which we screened 58 asymptomatic relatives from families with 21OHD patients and compared post-ACTH steroid phenotypes with subsequent genotypes. Post-ACTH 21DF, 17P, Fand (21DF + 17P)/F ratio segregate NC, HZ and wild-type (WT) phenotypes (subsequently genotyped) with some overlap. New receiver operating characteristic curve-defined cutoffs for post-ACTH 21DF, 17P and (21DF + 17P)/F ratio are 60 ng/dl, 310 ng/dl and 12 (unitless). Twenty-six of 33 HZ and all 6 NC (82.1%) had post-ACTH 21DF > 60and 17P > 310 ng/dl, whereas 17/19 WT (89.5%) had values below cutoffs. Post-ACTH 21DF and 17P had a strong positive correlation (r = .9558; p < .001). A (21DF + 17P)/F ratio > 12 correctly identified 36 of 39 HZ plus NC (92.3% sensitivity) with 84.2% specificity (16 of 19 WT). Given the high frequency of 21OHD HZ, the negative prediction of ratio values below 12 excludes heterozygosity in 99.8% and 99.1% for classic and NC mutations, respectively. Reassessed ACTH-stimulated 21DF and 17P cutoffs by LC-MS/MS (60 and 310 ng/dl, respectively) correctly recognised 82.5% HZ plus NC, but combined precursor-to-product ratio ([21DF + 17P]/F) cutoff of 12 was superior, identifying 92.3% HZ plus NC. Since one WT subject is an outlier (potential HZ), these values would be somewhat better reinforcing their utility for screening asymptomatic relatives at risk for 21OHD.

Heterozygous FXII deficiency is not associated with an increased incidence of thrombotic events: Results of a long term study

ObjectiveTo investigate the incidence of thrombotic events in patients heterozygous for FXII deficiency during a long observation period. Patients and methods103 heterozygotes for FXII deficiency, 49 female and 54 male were followed for 19.6 years (range 5–32 years). As controls 103 unaffected family members of same sex and similar age (±5 years) were enrolled. The thrombotic end points were: myocardial infarction, deep vein thrombosis and ischemic stroke.The mean Factor XII level in the heterozygotes was 48.5%: range (35–60%) that of control was 96.5% (range 70–155%).The heterozygotes showed one myocardial infarction, two deep vein thromboses and no ischemic stroke. The unaffected family members observed 2 myocardial infarctions, one deep vein thrombosis and one ischemic stroke.There were seven deliveries (five women) among the heterozygotes and six (five women) among the controls. Furthermore, four and five surgical procedures were carried out in the patient and in the control group, respectively.Immobilization times for surgical procedures or pregnancies were 50 days and 57 days for the heterozygotes and the unaffected family members, respectively.Heterozygotes for FXII deficiency did not show an increased incidence of thrombotic events as compared with unaffected family members during a long follow up.

Bleeding manifestations in heterozygotes with congenital FVII deficiency: a comparison with unaffected family members during a long observation period

ABSTRACTObjectives: To determine whether heterozygotes with FVII deficiency have a bleeding tendency or not.Patients and methods: Eighty-four patients (OK) heterozygous for FVII deficiency, at the onset of the study, were paired with unaffected family members and followed for a long period of time (mean 22.6 years) for the occurrence of bleeding. Diagnosis of heterozygosis had to be based on family studies, clotting, immunological assays and genetic analysis.Results: The mean FVII activity level was 0.51 IU/dl (range 35–65) and 94 IU/dl (range 88–118) in the heterozygotes and in the normal counterparts, respectively. Documented bleeding manifestations occurred in eight heterozygotes and in seven normal subjects. Statistical analysis of the difference was not significant. Bleeding manifestations were easy bruising, bleeding after tooth extractions, menorrhagia, epistaxis with no difference among the two groups. There was no strict correlation between bleeding and FVII activity levels.Conclusions: The study indicates that heterozygotes for FVII deficiency show rare bleeding manifestations which are also present in the unaffected family members with normal FVII levels. This indicates that Factor VII activity levels played no role in the occurrence of the bleeding symptoms. Furthermore, FVII levels of around 0.40 IU/dl are capable of assuring a normal hemostasis.

Heat shock transcription factor 1 protects against pressure overload-induced cardiac fibrosis via Smad3

Fibrotic cardiac muscle exhibits high stiffness and low compliance which are major risk factors of heart failure. Although heat shock transcription factor 1 (HSF1) was identified as an intrinsic cardioprotective factor, the role that HSF1 plays in cardiac fibrosis remains unclear. Our study aims to investigate the role of HSF1 in pressure overload-induced cardiac fibrosis and the underlying mechanism. HSF1 phosphorylation was significantly downregulated in transverse aortic constriction (TAC)-treated mouse hearts and mechanically stretched cardiac fibroblasts (cFBs). HSF1 transgenic (TG) mice, HSF1 deficient heterozygote (KO) mice, and their wild-type littermates were subjected to sham or TAC surgery for 4 weeks. HSF1 overexpression significantly attenuated pressure overload-induced cardiac fibrosis and dysfunction. Conversely, HSF1 KO mice showed deteriorated fibrotic response and cardiac dysfunction upon TAC. Moreover, we uncovered that overexpression of HSF1 protected against fibrotic response of cFBs to pressure overload. Mechanistically, we observed that the phosphorylation and the nuclear distribution of the Smad family member 3 (Smad3) were significantly decreased in HSF1-overexpressing mouse hearts, while being greatly increased in HSF1 KO mouse hearts upon TAC, compared to the control hearts, respectively. Similar alteration of Smad3 phosphorylation and nuclear distribution were found in isolated mouse cardiac fibroblasts and mechanically stretched cFBs. Constitutively active Smad3 blocked the anti-fibrotic effect of HSF1 in cFBs. Furthermore, we found a direct binding of phosphorylated HSF1 and Smad3, which can be suppressed by mechanical stress. In conclusion, the present study demonstrated for the first time that HSF1 acts as a novel negative regulator of cardiac fibrosis by blocking Smad3 activation.Key messagesHSF1 activity is decreased in fibrotic hearts.HSF1 overexpression attenuates pressure overload-induced cardiac fibrosis and dysfunction.Deficiency of HSF1 deteriorates fibrotic response and cardiac dysfunction upon TAC.HSF1 inhibits phosphorylation and nuclear distribution of Smad3 via direct binding to Smad3.Active Smad3 blocks the anti-fibrotic effect of HSF1.

Determinants of chronic obstructive pulmonary disease in patients with intermediate levels of alpha-antitrypsin.

We examined elderly heterozygotes for alpha-antitrypsin deficiency (phenotype MZ) to determine which of several factors might be associated with the development of chronic obstructive pulmonary disease (COPD). Elderly heterozygotes who smoked had a very high incidence of COPD (70 per cent), whereas homozygotes (phenotype MM) who smoked had a significantly lower incidence of COPD (35 per cent). There was no difference in the incidence of COPD between subjects with MM and MZ phenotypes who did not smoke. To determine if leukocyte enzymes were related to the development of COPD in elderly heterozygotes, we measured the activities of monocytic acid cathepsin, neutrophil acid cathepsin, neutral cathepsin, and elastase. The activities of these enzymes were not associated with the development of COPD or with smoking history in the heterozygotes. In conclusion, cigarette smoking seemed to be a significant determinant of the development of COPD in heterozygotes for alpha-antitrypsin deficiency, but the leukocyte enzyme actitivty that we studied was unrelated.

DNA hypermethylation and X chromosome inactivation are major determinants of phenotypic variation in women heterozygous for G6PD mutations.

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is an X-linked incompletely dominant enzyme deficiency that results from G6PD gene mutations. Women heterozygous for G6PD mutations exhibit variation in the loss of enzyme activity but the cause of this phenotypic variation is unclear. We determined DNA methylation and X-inactivation patterns in 71 G6PD-deficient female heterozygotes and 68 G6PD non-deficient controls with the same missense mutations (G6PD Canton c.1376G>T or Kaiping c.1388G>A) to correlate determinants with variable phenotypes. Specific CpG methylations within the G6PD promoter were significantly higher in G6PD-deficient heterozygotes than in controls. Preferential X-inactivation of the G6PD wild-type allele was determined in heterozygotes. The incidence of preferential X-inactivation was 86.2% in the deficient heterozygote group and 31.7% in the non-deficient heterozygote group. A significant negative correlation was observed between X-inactivation ratios of the wild-type allele and G6PD/6-phosphogluconate dehydrogenase (6PGD) ratios in heterozygous G6PD Canton (r=-0.657, p<0.001) or Kaiping (r=-0.668, p<0.001). Multivariate logistic regression indicated that heterozygotes with hypermethylation of specific CpG sites in the G6PD promoter and preferential X-inactivation of the wild-type allele were at risk of enzyme deficiency.

Reassessing an old claim: Natural selection of hemizygotes and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

Reassessing an old claim: Natural selection of hemizygotes and heterozygotes for G6PD deficiency in Africa by resistance to severe malaria

Buffering and proteolysis are induced by segmental monosomy in Drosophila melanogaster

Variation in the number of individual chromosomes (chromosomal aneuploidy) or chromosome segments (segmental aneuploidy) is associated with developmental abnormalities and reduced fitness in all species examined; it is the leading cause of miscarriages and mental retardation and a hallmark of cancer. However, despite their documented importance in disease, the effects of aneuploidies on the transcriptome remain largely unknown. We have examined the expression effects of seven heterozygous chromosomal deficiencies, both singly and in all pairwise combinations, in Drosophila melanogaster. The results show that genes in one copy are buffered, i.e. expressed more strongly than the expected 50% of wild-type level, the buffering is general and not influenced by other monosomic regions. Furthermore, long genes are significantly more highly buffered than short genes and gene length appears to be the primary determinant of the buffering degree. For short genes the degree of buffering depends on expression level and expression pattern. Furthermore, the results show that in deficiency heterozygotes the expression of genes involved in proteolysis is enhanced and negatively correlates with the degree of buffering. Thus, enhanced proteolysis appears to be a general response to aneuploidy.

Modification to reporting of qualitative fluorescent spot test results improves detection of glucose‐6‐phosphate dehydrogenase (G6PD)‐deficient heterozygote female newborns

The glucose-6-phosphate dehydrogenase (G6PD) fluorescent spot test (FST) is a useful screening test for G6PD deficiency, but is unable to detect heterozygote G6PD-deficient females. We sought to identify whether reporting intermediate fluorescence in addition to absent and bright fluorescence on FST would improve identification of mildly deficient female heterozygotes. A total of 1266 cord blood samples (705 male, 561 female) were screened for G6PD deficiency using FST (in-house method) and a quantitative enzyme assay. Fluorescence intensity of the FST was graded as either absent, intermediate or normal. Samples identified as showing absent or intermediate fluorescence on FST were analysed for the presence of G6PD mutations using TaqMan@SNP genotyping assays and direct nucleotide sequencing. Of the 1266 samples, 87 samples were found to be intermediate or deficient by FST (49 deficient, 38 intermediate). Of the 49 deficient samples, 48 had G6PD enzyme activity of ≤ 9.5 U/g Hb and one sample had normal enzyme activity. All 38 intermediate samples were from females. Of these, 21 had G6PD activity of between 20% and 60%, and 17 samples showed normal G6PD activity. Twenty-seven of the 38 samples were available for mutation analysis of which 13 had normal G6PD activity. Eleven of the 13 samples with normal G6PD activity had identifiable G6PD mutations. Glucose-6-phosphate dehydrogenase heterozygote females cannot be identified by FST if fluorescence is reported as absent or present. Distinguishing samples with intermediate fluorescence from absent and bright fluorescence improves detection of heterozygote females with mild G6PD deficiency. Mutational studies confirmed that 85% of intermediate samples with normal enzyme activity had identifiable G6PD mutations.

Unexpected glucose‐6‐phosphate dehydrogenase deficiency

A 50-year-old man with refractory intestinal T-cell lymphoma was started on combination chemotherapy (ifosfamide, methotrexate, l-asparaginase, etoposide, dexamethasone). Cotrimoxazole was commenced for pneumocystis prophylaxis after a normal glucose-6-phosphate dehydrogenase (G6PD) spot fluorescence screen [>4·5 iu/g haemoglobin (Hb)]. Initial tumour shrinkage was accompanied by renal impairment (creatinine 393 μmol/l, normal 67–109) and hyperuricaemia (1259 μmol/l, normal 260–530), and rasburicase (4·5 mg × 1 dose) was given for tumour lysis. Despite a dramatic fall in uric acid level (55 μmol/l), anaemia suddenly occurred (Hb fell from 113 g/l to 59 g/l), followed by hypotension and oliguria. Biochemical screening showed raised unconjugated bilirubin (41 μmol/l, normal <6) and lactate dehydrogenase (798 iu/l, normal 118–211). Intravascular haemolysis was confirmed by raised methaemalbumin (14·3 mg/l, normal <01·0) levels and haemoglobinuria. A peripheral blood film showed bite cells and abundant hemi-ghost cells (left), classical for oxidative haemolysis. The patient survived with transfusion, haemodialysis and supportive treatment, with complete renal recovery. A repeat G6PD enzyme assay on his stored blood sample showed a marginal G6PD level of 5·5 iu/g Hb, which lies within the range expected for female heterozygotes. His four brothers were all G6PD deficient (0·21–1·24 iu/g Hb). Using allele-specific polymerase chain reaction, a G6PD Kaiping allele (nt 1388 G→A) was detected in the patient and all siblings. Surprisingly the patient also carried a second normal G6PD allele, suggesting extra X chromosome material. On further questioning, the patient volunteered a history of azoospermia and bilateral absent vas deferens. There were no other abnormal features suggestive of Klinefelter syndrome. Karyotype analysis on stimulated peripheral blood lymphocytes and fluorescence in situ hybridization with an X whole chromosome painting probe (Oncor Inc., Gaithersburg, MD, USA) confirmed the presence of extra X chromosome material on the Y-chromosome (right, red arrow) in all 20 metaphases analysed: 46, XY.ish add(Y)(p11)(wcpX+). Hence the patient was an occult carrier of extra X chromosome material and a heterozygous carrier of G6PD deficiency. Deficiency of G6PD is the commonest red cell enzymopathy world-wide. It affects 4·8% of all Southern Chinese males, and is screened for at birth and before the commencement of oxidative medications. In female heterozygotes, random lyonization of the X chromosomes results in a mixture of normal and G6PD deficient red cells. The resultant average enzyme levels usually lie within the normal range. However female heterozygotes for G6PD deficiency can still suffer haemolysis as a result of skewed lyonization because of age, haemopoietic transplantation or clonal haemopoiesis. Without mandatory screening, this can cause unexpected severe haemolysis. Our case showed that a simple fluorescent screen might still be insufficient. Severe oxidative stresses because of a combination of drugs (cotrimoxazole and rasburicase) could still cause en masse destruction of the G6PD deficient subpopulation, resulting in life-threatening intravascular haemolysis. Hence, a quantitative enzyme level assay is a better option in areas endemic for G6PD deficiency.

Genetic Analysis of Scleropages formosus Golden Asian Arowana Using Microsatellite DNA

Asian arowana (Scleropages formosus) is a highly endangered fish species listed in Appendix 1 of CITES since1980.In order to explore the population genetic structure of golden Asian arowanas Scleropages formosus from the breeding population, of 26 fish sampled were genotyped at twenty microsatellite loci. The average allele number of 14 polymorphic microsatellites was 2.94 loci. The average observed heterozygosity was 0.446 ranging from 0.143 to 1.00, and the gene diversity was quite high (0.78).All these data suggest that middle level of genetic diversity existed in the golden Asian arowana population. Data showed the population somewhat departed from HWE, such as excessive and deficient heterozygote numbers.AMOVA analysis offered evidence of a weak genetic differentiation with 0.51% variation between samples.

2,8-dihydroxyadenine nephrolithiasis: from diagnosis to therapy

Adenine phosphoribosyltransferase (APRT, EC 2.4.2.7) deficiency is an enzymopathy of purine metabolism, which is inherited as an autosomal recessive trait. APRT is a salvage enzyme that normally catalyzes the conversion of adenine to adenosine monophosphate. APRT deficiency results in adenine accumulation with oxidation by xanthine dehydrogenase (XDH; EC 1.1.1.204) to 2,8-dihydroxyadenine (2,8-DHA) then excreted in urine. This compound is extremely insoluble and its crystallization can lead to stone formation and renal failure. The diagnosis of the disease is based on stone analysis by infrared spectroscopy or microscopic examination of urine, which may reveal typical 2,8-DHA crystals. The enzyme activity measurements in erythrocyte lysates will identify both homozygotes and heterozygotes for APRT deficiency. Molecular approach can identify mutations which are responsible of this inherited disease. Two types of deficit are commonly distinguished, depending on the level of residual APRT activity: type I, mainly observed in Caucasian subjects, in whom the enzyme activity is undetectable in homozygous patients and type II, found in Japanese patients who are able to form APRT but the enzyme activity is strikingly reduced because a low affinity for phosphoribosylpyrophosphate. The crystallization of 2,8-DHA and subsequent renal damages may be prevented with allopurinol therapy, a xanthine oxidase inhibitor. The role of the laboratory is crucial to detect APRT deficiency and to assess the efficacy of therapy, the objective being to avoid 2,8-DHA crystal formation.

MLP02 Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes

MLP02 Aromatic L-amino acid decarboxylase enzyme activity in deficient patients and heterozygotes

Heterozygous loss of platelet glycoprotein (GP) Ib-V-IX variably affects platelet function in velocardiofacial syndrome (VCFS) patients

Velocardiofacial syndrome (VCFS) is a common, phenotypically heterogeneous developmental disorder caused by an interstitial microdeletion within human chromosome 22q11. The deleted chromosomal region in >90% of VCFS patients includes the GPIb beta gene, encoding for one subunit of the platelet GPIb-V-IX receptor, which is critical for platelet adhesion under shear, and important in aggregation and thrombin-mediated activation. Complete loss of GPIb-V-IX due to autosomal recessive inheritance of two GPIb alpha, Ib beta or GP9 gene mutations, results in a severe bleeding disorder, Bernard-Soulier syndrome (BSS). In this study, twenty-one confirmedVCFS patients were analyzed for platelet morphological and functional alterations, resulting from the heterozygous loss of one GPIb beta gene allele. Compared to unaffected family members, VCFS patients showed a significant decrease in platelet count; VCFS platelet size and mean platelet volume were increased, but not as markedly as in BSS. As expected from obligatory heterozygotes for GPIb beta deficiency, VCFS patients showed reduced platelet GPIb-V-IX surface expression and total GPIb content, but with considerable variation between cases. Platelet function tested using the PFA-100 trade mark analyzer was impaired in 70% of patients. Platelet aggregation was reduced in response to a GPIb-dependent agonist, ristocetin, in 50% of VCFS patients, with 35% showing a reduced response to thrombin receptor activating peptide. Genomic screening was performed to exclude mutations of the subunit genes, indicating that these platelet abnormalities were due to GPIb beta heterozygosity and not spontaneous BSS. In conclusion, many VCFS patients have in-vitro defects in platelet function that may increase their risk of bleeding during surgery.

Genetic Polymorphism of Microsatellite DNA in Two Populations of Northern Sheatfish ( Silurus soldatovi)

In this article, population variations and genetic structures of two populations of northern sheatfish ( Silurus soldatovi) were analyzed using 24 microsatellite loci enriched from southern catfish ( S. meriaionalis Chen) by magnetic beads. Gene frequency ( P), observed heterozygosity ( Ho), expected heterozygosity ( He), polymorphism information contents ( PIC), and number of effective alleles ( Ne) were determined. One population was wild, ripe individuals collected from Heilongjiang River ( HNS); the other was cultured fry collected from Songhuajiang River ( SNS). The Hardy-Weinberg equilibrium (HWE) was tested by the genetic departure index ( d). The coefficient of gene differentiation G ST and Φ ST by AMOVA (Analysis of Molecular Variety) was imputed using Arlequin software in this study. In addition, a phylogenetic tree was constructed by UPGMA method based on the pairwise Nei's standard distances using PHYLIP. A total of 1 357 fragments with sizes ranging between 102 bp and 385 bp were acquired by PCR amplifications. The average number of alleles of the two populations was 8.875. Results indicated that these microsatellite loci were highly polymorphic and could be used as genetic markers. The mean values of the parameters P, Ho, He, PIC, and Ne were 0.165, 0.435, 0.758, 0.742, and 5.019 for HNS and 0.147, 0.299, 0.847, 0.764, and 5.944 for SNS, respectively. Although there were differences, there were no significant differentiations except for the locus HLJcf37. These populations to a certain extent deviated from HWE, such as excessive and deficient heterozygote numbers. The value of G ST was 0.078 and above 98% of the variation were differences among individuals within the population, so the variation between populations was insignificant. Cluster analysis also showed that the relationships among individuals were very close. In conclusion, the microsatellite markers that were developed through this study are useful for genetic analysis and the genetic culture that was proposed in this study has no significant impact on S. soldatovi.

Immunoglobulin deficiencies and susceptibility to infection among homozygotes and heterozygotes for C2 deficiency.

About 25% of C2-deficient homozygotes have increased susceptibility to severe bacterial infections. C2-deficient homozygotes had significantly lower serum levels of IgG2, IgG4, IgD, and Factor B, significantly higher levels of IgA and IgG3 and levels of IgG1 and IgM similar to controls. Type 1 (28 bp deletion in C2 exon 6 on the [HLA-B18, S042, DR2] haplotype or its fragments) and type II (non-type I) C2-deficient patients with increased susceptibility to bacterial infection had significantly lower mean levels of IgG4 (p < 0.04) and IgA (p < 0.01) than those without infections (who had a higher than normal mean IgA level) but similar mean levels of other immunoglobulins and Factor B. Of 13 C2-deficient homozygotes with infections, 85% had IgG4 deficiency, compared with 64% of 25 without infections. IgD deficiency was equally extraordinarily common among infection-prone (50%) and noninfection-prone (70%) homozygous type I C2-deficient patients. IgD deficiency was also common (35%) among 31 type I C2-deficient heterozygotes (with normal or type II haplotypes), but was not found in 5 type II C2-deficient heterozygotes or 1 homozygote. Thus, C2 deficiency itself is associated with many abnormalities in serum immunoglobulin levels, some of which, such as in IgG4 and IgA, may contribute to increased susceptibility to infection. In contrast, IgD deficiency appears not to contribute to increased infections and appears to be a dominant trait determined by a gene or genes on the extended major histocompatibility complex (MHC) haplotype [HLA-B 18, S042, DR2] (but probably not on type II C2-deficient haplotypes) similar to those previously identified on [HLA-B8, SC01, DR3] and [HLA-B18, F1C30, DR3].

Allotypic variation of the third component of complement in an aboriginal tribe in Taiwan.

In 1981, we reported a case of complete absence of C3 in an aborigine (Atayal tribe) girl in Taiwan. Since then, serum C3 level and allotypes have been evaluated in 1,372 Atayal people. The incidence of C3 deficient heterozygote was 15.7%. All the C3 allotype was C3S. The gene frequency was 1. The Atyayal population seems more akin to Mongol populations than to Caucasians.

Acute hemolysis and severe neonatal hyperbilirubinemia in glucose-6-phosphate dehydrogenase–deficient heterozygotes

Two premature female infants had severe hyperbilirubinemia caused by hemolysis. Both neonates were heterozygotes for the glucose-6-phosphate dehydrogenase Mediterranean mutation as determined by DNA analysis. Glucose-6-phosphate dehydrogenase–deficient heterozygotes may be susceptible to the complications of this enzyme deficiency. (J Pediatr 2001;139:137-40)

Genetic determinants of hyperhomocysteinaemia: the roles of cystathionine beta-synthase and 5,10-methylenetetrahydrofolate reductase.

Over the last decade mild hyperhomocysteinaemia has widely been recognised as a new risk factor for arteriosclerosis and thrombosis. Main regulating enzymes of homocysteine (Hcy) metabolism are cystathionine beta-synthase (CBS), methionine synthase and methylenetetrahydrofolate reductase (MTHFR). Early studies on patients with vascular disease described elevated Hcy concentrations after methionine loading and decreased CBS activity, resembling heterozygotes for CBS deficiency. Therefore, heterozygosity for CBS deficiency was proposed as the main cause of mild hyperhomocysteinaemia. However, more recent enzymatic and molecular genetic studies have demonstrated that heterozygosity for CBS deficiency is not or only a very minor cause of mild hyperhomocysteinaemia in vascular disease. We discovered two common genetic causes of mild hyperhomocysteinaemia, the 677C > T and the 1298A > C mutations in the coding region of MTHFR. The 677C > T mutation causes reduced enzyme activity with thermolabile protein properties, elevated Hcy and low-normal or decreased plasma folate levels. The 1298A > C mutation relates also to decreased enzyme activity, but not to thermolabile protein, and Hcy and folate levels are not influenced. However, compound heterozygosity for these two mutations, i.e. individuals with the 677CT/1298AC genotype, have elevated Hcy and decreased plasma folate levels. Gene-enviroment interactions between 677C > T and folate is demonstrated in individuals with the 677TT genotype. Those with low-normal folate have elevated Hcy, whereas those with high-normal folate have normal Hcy concentrations. The elevated Hcy levels due to these mutations can be normalised by administration of folate, but whether folate reduces the risk of cardiovascular disease remains to be established. Heterozygosity for cystathionine beta-synthase deficiency is a minor cause of hyperhomocysteinaemia. The current data on mutations in the methylenetetrahydrofolate reductase gene do not tell us whether elevated plasma homocysteine plays a causal role in vascular disease. Low cellular vitamin status may be a possible cause and homocysteine may just be a marker for this situation.