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PubMed1999

17Beta-hydroxysteroid dehydrogenase-3 deficiency: diagnosis, phenotypic variability, population genetics, and worldwide distribution of ancient and de novo mutations.

17Beta-hydroxysteroid dehydrogenase-3 (17betaHSD3) deficiency is an autosomal recessive form of male pseudohermaphroditism caused by mutations in the HSD17B3 gene. In a nationwide study on male pseudohermaphroditism among all pediatric endocrinologists and clinical geneticists in The Netherlands, 18 17betaHSD3-deficient index cases were identified, 12 of whom initially had received the tentative diagnosis androgen insensitivity syndrome (AIS). The phenotypes and genotypes of these patients were studied. Endocrine diagnostic methods were evaluated in comparison to mutation analysis of the HSD17B3 gene. RT-PCR studies were performed on testicular ribonucleic acid of patients homozygous for two different splice site mutations. The minimal incidence of 17betaHSD3 deficiency in The Netherlands and the corresponding carrier frequency were calculated. Haplotype analysis of the chromosomal region of the HSD17B3 gene in Europeans, North Americans, Latin Americans, Australians, and Arabs was used to establish whether recurrent identical mutations were ancient or had repeatedly occurred de novo. In genotypically identical cases, phenotypic variation for external sexual development was observed. Gonadotropin-stimulated serum testosterone/androstenedione ratios in 17betaHSD3-deficient patients were discriminative in all cases and did not overlap with ratios in normal controls or with ratios in AIS patients. In all investigated patients both HSD17B3 alleles were mutated. The intronic mutations 325 + 4;A-->T and 655-1;G-->A disrupted normal splicing, but a small amount of wild-type messenger ribonucleic acid was still made in patients homozygous for 655-1;G-->A. The minimal incidence of 17betaHSD3 deficiency in The Netherlands was shown to be 1: 147,000, with a heterozygote frequency of 1:135. At least 4 mutations, 325 + 4;A-->T, N74T, 655-1;G-->A, and R80Q, found worldwide, appeared to be ancient and originating from genetic founders. Their dispersion could be reconstructed through historical analysis. The HSD17B3 gene mutations 326-1;G-->C and P282L were de novo mutations. 17betaHSD3 deficiency can be reliably diagnosed by endocrine evaluation and mutation analysis. Phenotypic variation can occur between families with the same homozygous mutations. The incidence of 17betaHSD3 deficiency is 0.65 times the incidence of AIS, which is thought to be the most frequent known cause of male pseudohermaphroditism without dysgenic gonads. A global inventory of affected cases demonstrated the ancient origin of at least four mutations. The mutational history of this genetic locus offers views into human diversity and disease, provided by national and international collaboration.

17-Hydroxysteroid Dehydrogenases↗
PubMed1999

Frequency of BRCA1 mutation 5382insC in German breast cancer patients.

OBJECTIVE: The aim of the study was to determine the frequency of the BRCA1 mutation 5382insC in German breast cancer patients with and without prior knowledge of a family history of breast cancer. METHODS: Two groups of breast cancer patients were tested for the presence or absence of the 5382insC mutation using a PCR primer mismatch assay. A sample of 248 patients unrelated by genealogy was selected based on a history of breast and/or ovarian cancer in the families. In addition, a population-based sample of 800 unselected breast cancer patients was included in the analysis. Three intragenic DNA markers D17S1323, D17S1322, and D17S855, located at BRCA1 introns 12, 19, and 20, respectively, were utilized for allelic association studies as well as for haplotype analysis in 4 breast/ovarian cancer families. RESULTS: The 5382insC mutation was identified in 10/248 (4.0%) familial breast cancer patients and in 8/800 (1.0%) unselected cases. Allelic association studies and haplotype analysis revealed an association of allele Nos. "6" at D17S1323 (chi2 value = 9.34, P = 0.007), "5" at D17S1322 (chi2 value = 3.62, P = 0.171), and "4" at D17S855 (chi2 value = 11.34, P = 0. 002) with the mutation 5382insC. CONCLUSION: 5382insC constitutes a frequent BRCA1 mutation in German breast cancer patients. The significant allelic association between this mutation and two intragenic DNA markers (D17S1323, D17S855) and the elevated allele frequency at marker D17S1322 suggest an ancient founder in the German breast cancer population. The PCR primer mismatch assay described herein provides a rapid and reliable detection method for the recurrent 5382insC mutation and will be useful for the analysis of large breast cancer populations.

Adult↗
PubMed1992

Mutation analysis and prenatal diagnosis in a Lesch-Nyhan family showing non-random X-inactivation interfering with carrier detection tests.

A nonsense mutation at the CpG-site in the codon for Arg(169) in the gene for hypoxanthine phosphoribosyltransferase (hprt) was identified by genomic polymerase chain reaction (PCR) and DNA sequencing in cultured fibroblasts from two brothers with Lesch Nyhan's syndrome. The recurrence of mutation at this CpG-site in several unrelated Lesch-Nyhan families suggests that deamination of 5-methylcytosine is a possible mechanism for mutagenesis. The level of hprt-mRNA in the fibroblasts of the patients was similar to that in healthy controls, whereas hprt-enzyme activity was not detectable. The mutation in this family was also identified in five female relatives and prenatally in a male fetus. Unexpectedly, results from hair follicle analyses and fibroblast selection studies in 8-azaguanine and 6-thioguanine medium showed a non-carrier phenotype in three of the female heterozygotes, whereas X-inactivation mosaicism was demonstrated in one heterozygote. A possible explanation for the apparent non-random X-inactivation in this family is the co-existence of the hprt mutation with an undefined X-linked lethal mutation. This observation is of practical relevance for carrier detection in other Lesch-Nyhan families.

Base Sequence↗
PubMed2002

Prenatal diagnosis of a lethal form of Netherton syndrome by SPINK5 mutation analysis.

Netherton syndrome (NS) is a severe autosomal recessive ichthyosis with no specific treatment or prenatal diagnosis available at present. The recent identification of SPINK5, which encodes a serine protease inhibitor, as the defective gene enables DNA based prenatal diagnosis to be carried out. Here we report the first direct molecular prenatal diagnosis of a lethal form due to a recurrent SPINK5 mutation in three consanguineous Turkish families. XmnI restriction enzyme digestion and DNA sequencing demonstrated that each deceased affected child was homozygous for mutation 153delT inherited from each parent. Analysis of fetal DNA from amniotic fluid cells in Family 1 and from a chorionic villus sampling in Family 3 showed that the fetus was heterozygous for 153delT in both cases. The pregnancies were carried to term and the newborns were unaffected. In Family 2, fetal DNA analysis from chorionic villus biopsy showed in a first pregnancy that the fetus was homozygous for 153delT. The pregnancy was terminated at 13 weeks and DNA analysis of fetal keratinocytes confirmed the prenatal prediction. In a second pregnancy in Family 2, fetal DNA analysis showed heterozygosity for 153delT, and the pregnancy was continued. Direct SPINK5 mutation analysis in families at risk for NS represents the first early, rapid and reliable method for prenatal diagnosis of this life threatening form of ichthyosis.

Amniocentesis↗
PubMed2000

Recurrent myoglobinuria due to a nonsense mutation in the COX I gene of mitochondrial DNA.

OBJECTIVE: To elucidate the molecular basis of a mitochondrial myopathy associated with recurrent myoglobinuria and cytochrome c oxidase (COX) deficiency in muscle. BACKGROUND: Recurrent myoglobinuria is typically seen in patients with inborn errors of carbohydrate or lipid metabolism, the main sources of energy for muscle contraction. Relatively little attention has been directed to defects of the mitochondrial respiratory chain in patients with otherwise unexplained recurrent myoglobinuria. METHODS: Having documented COX deficiency histochemically and biochemically in the muscle biopsy from a patient with exercise-induced recurrent myoglobinuria, the authors sequenced the three mitochondrial DNA (mtDNA)-encoded COX genes, and performed restriction fragment length polymorphism analysis and single-fiber PCR. RESULTS: The authors identified a nonsense mutation (G5920A) in the COX I gene in muscle mtDNA. The mutation was heteroplasmic and abundantly present in COX-negative fibers, but less abundant or absent in COX-positive fibers; it was not found in blood or fibroblasts from the patient or in blood samples from the patient's asymptomatic mother and sister. CONCLUSIONS: The G5920A mutation caused COX deficiency in muscle, explaining the exercise intolerance and the low muscle capacity for oxidative phosphorylation documented by cycle ergometry. The sporadic occurrence of this mutation in muscle alone suggests that it arose de novo in myogenic stem cells after germ-layer differentiation. Mutations in mtDNA-encoded COX genes should be considered in patients with recurrent myoglobinuria.

Adult↗
PubMed2003

Recurrent pregnancy loss due to familial and non-familial habitual molar pregnancy.

OBJECTIVES: To present a series of women with recurrent molar pregnancies, including rare familial cases, and discuss etiology and treatment options. METHODS: We performed a detailed clinical evaluation and pedigree analysis of five Egyptian women with recurrent pregnancy loss due to molar pregnancy. RESULTS: The women had a history of four to nine consecutive hydatidiform moles but of no viable pregnancies. Two of the women had molar pregnancies with different husbands who themselves had viable offspring from previous wives; and three of them, who belonged to a family with extensive intermarriage, had a pedigree consistent with an autosomal recessive maternal-effect mutation. CONCLUSIONS: Recurrent pregnancy loss due to habitual molar pregnancy is uncommon and familial cases are extremely rare. The etiology of this disorder is not well understood but likely results from a maternal-effect mutation. Management options are limited, especially for couples who desire to have their own genetic offspring.

Abortion, Habitual↗
PubMed1998

Venous thrombosis in older people: prevalence of the factor V gene mutation Q506.

OBJECTIVES: Old age is usually considered to be a risk factor for venous thromboembolism, in conjunction with other factors such as heart failure, major surgery, cancer, long-term immobilization, and antiphospholipid antibodies. Genetic risk factors, especially inherited deficiencies in coagulation inhibitors, also play a role in the pathogenesis of thrombosis, but these are usually diagnosed in thrombophilic patients before the age of 50. The factor V Q506 mutation, responsible for activated protein C resistance, was recently linked to thromboembolic disease. We therefore investigated the prevalence of biological risk factors in older hospital patients with venous thromboembolism. DESIGN: A 2-year study period. SETTING: Ivry sur Seine (Paris), France. PARTICIPANTS: Seventy-nine geriatric patients (60 women and 19 men, mean age 83+/-6.8 years, range 70-102 years) who had had at least one proven episode of venous thromboembolism were enrolled over a 2-year period. MEASUREMENTS: Lupus anticoagulant and antithrombin (AT), protein C (PC), and protein S (PS) levels were determined in plasma. The factor V Q506 mutation was detected on genomic DNA. RESULTS: Lupus anticoagulant was detected in two women, one of whom also had a high level of anticardiolipin IgG, leading to the diagnosis of an antiphospholipid syndrome. No hereditary deficiency in AT, PC, or PS was found, but one patient had an acquired AT deficiency. Interestingly, nine of the 79 patients (11.4%, six women and three men) were heterozygous for the factor V Q506 mutation, although none were homozygous. The only major risk factor for thrombosis identified in these patients was prolonged immobilization in four cases. Four of the nine patients who were heterozygous for the factor V Q506 mutation had recurrent thromboembolism, and two of these patients had been immobilized for long periods. CONCLUSIONS: This study confirms that hereditary deficiencies in coagulation inhibitors, and the lupus anticoagulant, are rarely involved in the pathogenesis of venous thromboembolism in older subjects. In contrast, the factor V Q506 mutation was frequently associated with thrombosis (11.4% of our patients) and should, therefore, be considered an important risk factor in the older people.

Activated Protein C Resistance↗
PubMed1993

Origin of the expansion mutation in myotonic dystrophy.

Myotonic dystrophy (DM) is caused by the expansion of a CTG trinucleotide repeat. The mutation is in complete linkage disequilibrium with a nearly two-allele insertion/deletion polymorphism, suggesting a single origin for the mutation or predisposing mutation. To trace this-ancestral event, we have studied the association of CTG repeat alleles in a normal population to alleles of the insertion/deletion polymorphism and of a (CA)n repeat marker 90 kilobases from the DM mutation. The results strongly suggest that the initial predisposing event(s) consisted of a transition from a (CTG)5 allele to an allele with 19 to 30 repeats. The heterogeneous class of (CTG)19-30 alleles which has an overall frequency of about 10%, may constitute a reservoir for recurrent DM mutations.

Alleles↗
PubMed1996

A recurrent clonotype in the spontaneous anti-IgG2a rheumatoid factor response of lpr/lpr mice.

We generated mice transgenic for a VH gene that partially encodes an anti-IgG2a rheumatoid factor. Such transgenic VH genes recombine at a low frequency with the endogenous Igh locus in mice, giving rise to a small number of B cells that express heavy chains partially encoded by the transgene. The transgenes were crossed onto an lpr/lpr background, and hybridomas were generated from the resulting mice at 3 to 6 mo of age. Analysis of the anti-IgG2a- producing hybridomas obtained revealed that none expressed the transgenic VH. Surprisingly, however, most of the mice yielded multiple anti-IgG2a hybridomas that expressed VH genes comprised of a single VH gene segment, D regions with highly homologous 5' ends encoding CDR3 regions of identical length, and the JH4 segment. Expressed light chain diversity among these hybridomas was also highly restricted; most expressed a single V kappa gene segment. All of the hybridomas expressed members of the V kappa 19/28 family. Many of the VH genes contained a low frequency of somatic mutation. The recurrence of this family of V regions is not due to an indirect transgene effect or to effects of the genetic background used to construct the mice, as hybridomas expressing the predominant V gene segment combination were also isolated from a transgene-negative lpr/lpr littermate and from MRL lpr/lpr mice. These data contrast with the previous findings of others that while the spontaneous rheumatoid factor response of lpr/lpr mice was oligoclonal, recurrent clonotypes were not apparent, and the VH and V kappas encoding these rheumatoid factors contained a high frequency of somatic mutation whose distribution and type were indicative of Ag-driven selection.

Animals↗
PubMed2004

Ectopia lentis phenotypes and the FBN1 gene.

Mutations of the fibrillin-1 (FBN1) gene on chromosome 15 have been described in patients with classical Marfan syndrome (MFS), neonatal MFS, the "MASS" phenotype, autosomal dominant ascending aortic aneurysms, autosomal dominant ectopia lentis (EL), Marfanoid skeletal features [Milewicz et al., 1995: J Clin Invest 95:2373-2378], familial arachnodactyly, Shprintzen-Goldberg syndrome [Hayward et al., 1994: Mol Cell Probes 8:325-327; Furthmayr and Francke, 1997: Semin Thorac Cardiovasc Surg 9:191-205], and severe progressive kyphoscoliosis [Adès et al., 2002: Am J Med Genet 109:261-270]. We report the use of denaturing high performance liquid chromatography (DHPLC) to facilitate the characterization of a previously elusive FBN1 mutation in the large autosomal dominant EL kindred described by Edwards et al. [1994: Am J Med Genet 53:65-71]. This isolated EL kindred remains the largest for which detailed clinical data is available. Nine years on, we present an update of the clinical status of the family. We report a recurrent FBN1 mutation, R240C, in the kindred. This mutation has been reported three times before, once in a family with classic MFS [Loeys et al., 2001: Arch Intern Med 161:2447-2454], once in one member of a multi-generation EL kindred, [Körkkö et al., 2002: J Med Genet 39:34-41], and once in an adult from a familial EL kindred who had EL, and involvement of the integument, without cardiovascular involvement [Comeglio et al., 2002: Br J Ophthalmol 86:1359-1362]. This is the second report of the R240C mutation in association with isolated EL, and supports the existing evidence that the R240C mutation can result in two quite distinct, yet related, phenotypes. It also raises the possibility that R240C may prove to be a relative mutational "hot-spot" for isolated EL. We review the current literature regarding EL (isolated and other) and FBN1 mutations.

Adult↗
PubMed2002

Factors associated with viral breakthrough in lamivudine monoprophylaxis of hepatitis B virus recurrence after liver transplantation.

This study aimed to investigate the factors associated with viral breakthrough among liver transplant recipients who receive lamivudine monoprophylaxis. Consecutive patients receiving liver transplantation for HBV-related liver disease from June 1999 to October 2000 were studied. All patients received lamivudine 100 mg daily pre- and post-transplant. Serum samples were collected before lamivudine treatment, before liver transplantation, and then every 3-6 months after liver transplantation. Lamivudine-resistant mutations at the YMDD motif of HBV P gene were detected by direct sequencing and HBV DNA was quantified by real-time polymerase chain reaction (PCR). Ten patients, 7 males and 3 females, aged 50.5 +/- 7.9 years, were studied. Three patients had fulminant hepatitis and 7 patients had end-stage cirrhosis before liver transplantation. Lamivudine was started at 4.5 (range 0-40) weeks before liver transplantation. The median post-transplant follow-up was 16 (range 12-23) months. Four patients developed YMDD mutations 10.5 (0-16) months after transplantation with relapse of viraemia (median 1,294, range 51-3,135 MEq/ml). All patients who developed YMDD mutants had end-stage liver cirrhosis, and HBV DNA were detectable on the day of liver transplantation (median 0.62, range 0.086-1.63 MEq/ml). On the contrary, all 3 patients transplanted for fulminant hepatitis did not have YMDD mutation. Among the 3 end-stage cirrhotic patients who had negative HBV DNA before liver transplantation, none developed YMDD mutation. In conclusion, patients transplanted for fulminant hepatitis B and cirrhotic patients in whom HBV DNA could be rendered PCR negative before liver transplantation are unlikely to develop YMDD mutation on lamivudine monoprophylaxis.

Adult↗
PubMed1998

Factor V Leiden mutation as a risk factor for recurrent pregnancy loss.

BACKGROUND: Recurrent pregnancy loss may result from hypercoagulability. OBJECTIVE: To determine whether women with factor V Leiden mutation, a common inherited defect of coagulation, are at increased risk for recurrent pregnancy loss. DESIGN: Case-control study. SETTING: University hospital. PATIENTS: 113 consecutive women referred for evaluation of recurrent spontaneous abortion (case-patients) and 437 postmenopausal women with at least one successful pregnancy and no history of pregnancy loss (controls). An additional survey of 387 postmenopausal women with at least one pregnancy loss was also conducted. MEASUREMENTS: Prevalence of factor V Leiden mutation determined by a second-generation screening test for resistance to activated protein C with genetic confirmation of all borderline and low-value results. RESULTS: Prevalence of the factor V Leiden mutation was greater among case-patients (8.0%) than among controls (3.7%) (odds ratio, 2.3 [95% CI, 1.0 to 5.2]; P = 0.050). In the subgroup of case-patients with three or more pregnancy losses and no successful pregnancies, prevalence of the mutation was 9.0% (odds ratio, 2.6 [CI, 1.0 to 6.7]; P = 0.048). Among the additional women surveyed, the prevalence of the mutation in those with three or more pregnancy losses (7.5%) was almost identical to that in case-patients. Thus, in all evaluated women with several pregnancy losses, the prevalence of factor V Leiden was increased 2.2-fold (P = 0.026). CONCLUSION: These data are compatible with the hypothesis that factor V Leiden mutation may play a role in some cases of unexplained recurrent pregnancy loss.

Abortion, Habitual↗
PubMed1998

Mutation hot spots in 5q31-linked corneal dystrophies.

Mutations in the BIGH3 gene on chromosome 5q31 cause four distinct autosomal dominant diseases of the human cornea: granular (Groenouw type I), Reis-Bücklers, lattice type I, and Avellino corneal dystrophies. All four diseases are characterized by both progressive accumulation of corneal deposits and eventual loss of vision. We have identified a specific recurrent missense mutation for each type of dystrophy, in 10 independently ascertained families. Genotype analysis with microsatellite markers surrounding the BIGH3 locus was performed in these 10 families and in 5 families reported previously. The affected haplotype could be determined in 10 of the 15 families and was different in each family. These data indicate that R555W, R124C, and R124H mutations occurred independently in several ethnic groups and that these mutations do not reflect a putative founder effect. Furthermore, this study confirms the specific importance of the R124 and R555 amino acids in the pathogenesis of autosomal dominant corneal dystrophies linked to 5q.

Chromosome Mapping↗
PubMed2006

Transient hemophagocytosis with deficient cellular cytotoxicity, monoclonal immunoglobulin M gammopathy, increased T-cell numbers, and hypomorphic NEMO mutation.

X-linked osteopetrosis, anhydrotic ectodermal dysplasia, and immunodeficiency (XL-O-EDA-ID) is a disorder that is caused by hypomorphic mutations in the nuclear factor kappaB essential modulator (NEMO). These mutations lead to an impaired NF-kappaB activation. In vitro analyses and studies in animal models show that inhibition of NF-kappaB leads to a decrease of cytokine production and T-cell proliferation. Patients classically display poor or delayed inflammatory response to infections. We describe a boy with XL-O-EDA-ID, 1167-1168insC NEMO mutation, and recurrent infections. In early infancy, he experienced hemophagocytosis with transient deficiency of natural killer activity. Increased immunoglobulin M levels in blood resulted from a monoclonal immunoglobulin M gammopathy. Blood T-cell numbers were constantly increased, most probably resulting from a peripheral T-cell expansion. Our observations suggest that patients with hypomorphic NEMO mutations and repeated infections may experience inflammatory dysregulation.

Bacterial Infections↗
PubMed2006

Acute respiratory distress syndrome with transiently impaired left ventricular function and Torsades de Pointes arrhythmia unmasking congenital long QT syndrome in a 25-yr-old woman.

We report a case of recurrent episodes of Torsades de Pointes arrhythmia in the setting of transiently impaired left ventricular ejection fraction, acute respiratory distress syndrome, transient hypokalaemia and QT-prolonging drugs, in a previously healthy 25-yr-old female patient. In the course of the clinical and genetic work-up this patient was newly diagnosed with a mutation in KCNH2 encoding the alpha-subunit of the human repolarizing potassium channel I(Kr). This case report illustrates the multivariate nature of long-QT syndrome, and emphasizes the usefulness of a pharmacological test for repolarization abnormalities.

Adult↗
PubMed1999

The C677T MTHFR gene mutation is not predictive of risk for recurrent fetal loss.

We have investigated the potency of the C677T mutation in the methylene tetrahydrofolate reductase (MTHFR) gene as a genetic risk factor in women with a history of early (</=12 weeks gestation) and/or late (>12 weeks gestation) recurrent miscarriage (three or more consecutive pregnancy losses). Fifty-seven of the total 173 (32. 9%) patients were heterozygous for the MTHFR mutation, 14/173 (8.1%) were homozygous (allele frequency 0.25). The prevalence of the MTHFR mutation in these women did not differ significantly from that in the control group of parous women with uneventful pregnancies, where 30/67 (44.8%) were heterozygous and 6/67 (9.0%) homozygous for the mutation (allele frequency 0.31; odds ratio for homozygous T/T 0.90, 95% CI 0.30-2.4). There was no association between the trimester of pregnancy loss and MTHFR genotype. We conclude that the C677T MTHFR mutation is not a risk predictor in women with a history of early or late recurrent miscarriage.

Abortion, Habitual↗
PubMed1998

Recurrent acyclovir-resistant herpes simplex in an immunocompromised patient: can strain differences compensate for loss of thymidine kinase in pathogenesis?

To investigate how acyclovir-resistant (ACVr) herpes simplex virus (HSV) evades drug therapy and causes disease, HSV-1 isolates from a bone marrow transplant (BMT) patient were studied. The patient developed ACVr disease after an initial BMT and, following a second BMT, reactivated ACVr HSV despite high-dose acyclovir prophylaxis. ACVr isolates from each episode contained the same point mutation in the viral thymidine kinase (tk) gene, documenting the emergence, latency, and reactivation of this mutant. The mutants were exceedingly impaired for TK activity in sensitive enzyme, plaque autoradiography, and drug-susceptibility assays. Nevertheless, these mutants and a tk deletion mutant constructed in the same genetic background reactivated from latency in mouse trigeminal ganglia, in contrast to similar mutants from laboratory strains. It is hypothesized that alleles in the clinical isolate compensate for the loss of TK in this animal model. Such genetic variability may be important for ACVr disease in humans.

Acyclovir↗