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PubMed2006

First-trimester fetal nuchal translucency and inherited metabolic disorders.

OBJECTIVES: To assess the association between inherited metabolic disorders and nuchal translucency (NT) measurements. METHODS: The NT measurements obtained from 66 fetuses at high risk for metabolic diseases prior to chorionic villus sampling (CVS) were retrospectively analysed. RESULTS: NT was found to be within the normal range in all of the 13 affected fetuses, which included three with Gaucher disease, two with glycogenosis type II, two with mucopolysaccharidosis type I and six others with Krabbe disease, metachromatic leukodystrophy, mucopolysaccharidosis type II, Niemann-Pick A disease, Pelizaeus-Merzbacher disease and sialidosis, respectively. An increased nuchal thickness was found only in one fetus affected with trisomy 21 but not affected with mucopolysaccharidosis type II. CONCLUSION: NT appears to have a limited role in identifying affected fetuses in pregnancies at high risk for inherited metabolic disorders. NT may be normal in early pregnancy even for fetuses affected with conditions known to be associated with non-immune hydrops fetalis.

Adult↗
PubMed2002

Perinatal imaging findings of inherited Sotos syndrome.

OBJECTIVES: Although most cases of Sotos syndrome are sporadic, familial cases have been described. In familial cases, the most likely mode of inheritance is autosomal dominant with variable expressivity. We present the perinatal imaging findings of an inherited case. CASE: This was the second pregnancy of a 32-year-old woman with Sotos syndrome. She had given birth to her first child with macrocephaly, ventriculomegaly, macrocisterna magna and neonatal death at 28 weeks' gestation. During this pregnancy, prenatal ultrasonography at 18 weeks' gestation showed only mild dilatation of lateral ventricles. The pregnancy was uneventful until 31 weeks' gestation when fetal macrocephaly, right hydronephrosis, and polyhydramnios began to develop. At 33 weeks' gestation, dilatation of the third ventricle and fetal overgrowth were obvious. At 34 weeks' gestation, macrodolichocephaly, hypoplasia of the corpus callosum, enlargement of the lateral ventricles with prominent occipital horns, and macrocisterna magna were noted. At 36 weeks' gestation, a male baby was delivered with macrodolichocephaly, frontal bossing and a facial gestalt of Sotos syndrome. Birth weight was 3822 g, length 55 cm, and occipitofrontal head circumference 41 cm (all > 97th centile). The magnetic resonance imaging (MRI) scans demonstrated enlargement of the lateral ventricles, the trigones, and the occipital horns, hypoplasia of the corpus callosum, a persistent cavum septum pellucidum and cavum vergae, and macrocisterna magna. CONCLUSIONS: Fetuses at risk for Sotos syndrome may present abnormal sonographic findings of the brain and the skull in association with overgrowth, unilateral hydronephrosis and polyhydramnios in the third trimester. Perinatal MRI studies aid in confirmation of the diagnosis.

Adult↗
PubMed2003

Idiopathic fetal intrauterine growth restriction: a possible inheritance pattern.

OBJECTIVE: This study was conducted to assess if the delivery of a previous growth-retarded (IUGR) fetus increases the risk of having an IUGR fetus in subsequent pregnancies and to explore if a familial pattern of transmission is involved. METHODS: Seventy consecutive multiparous women whose fetus was IUGR (group 1) and 70 controls (group 2) were enrolled in this study. RESULTS: The proportion of women who developed preeclampsia (9 versus 2, p = 0.05) and who had delivered an IUGR fetus in a previous pregnancy (20 versus 4, p < 0.05) were higher in group 1 than in group 2. There was no difference in the incidence of chronic hypertension, diabetes, smoking, substance or alcohol abuse, and HIV infection between the groups. After adjustment for preeclampsia, the delivery of a previous IUGR fetus remained a risk factor for having a subsequent IUGR fetus [Odds ratio = 6.7 (CI 2.15-21.22), p < 0.01]. Pedigree analysis conducted in 15 families revealed a familial cluster of IUGR infants in all families that were investigated. In 9 out of 15 families, a dominant pattern of inheritance of IUGR was observed while the remaining families were more heterogeneous. In one family, a balanced carrier of chromosome 7 inversion generated a malformed fetus and two IUGR infants. CONCLUSIONS: This study clarifies that IUGR may be an inherited genetic condition and emphasizes that a knowledge of the family history and of the parental karyotype may be helpful in the prevention of both fetal malformations and adverse neonatal morbidity in subsequent low birth weight infants.

Adult↗
PubMed2006

Analysis of the cerebellar proteome in a transgenic mouse model of inherited prion disease reveals preclinical alteration of calcineurin activity.

Inherited prion diseases are linked to insertional and point mutations in the prion protein (PrP) gene, which favor conversion of PrP into a conformationally altered, pathogenic isoform. The cellular mechanism by which this process causes neurological dysfunction is unknown. Transgenic (Tg) (PG14) mice express a mouse PrP homolog of a nine-octapeptide insertion associated with an inherited prion disorder. These mice develop a progressive neurological syndrome characterized by ataxia and cerebellar atrophy due to synaptic degeneration in the molecular layer and massive apoptosis of granule neurons. To investigate the molecular events that may contribute to neurological dysfunction, we carried out a differential proteomic analysis of cerebella from Tg(PG14) mice at the preclinical, onset, and symptomatic phases of their neurological illness. 2-D maps of cerebellar proteins from Tg(PG14) mice were compared to those obtained from age-matched Tg(WT) mice that express wild-type PrP and remain healthy. Proteins whose levels were significantly modified in at least one stage of the Tg(PG14) disease were identified by PMF. Analysis detected a preclinical decrease of the calcium/calmodulin-dependent phosphatase calcineurin (CaN) in granule neurons, suggesting that dysregulation of CaN activity induced by mutant PrP may be responsible for the cerebellar dysfunction in Tg(PG14) mice.

Animals↗
PubMed2005

Inheritance of resistance and cross-resistance to deltamethrin in Plutella xylostella (Lepidoptera: Plutellidae) from Pakistan.

A field population of Plutella xylostella (L) from Pakistan was found to be highly resistant to deltamethrin (>500-fold) but had little or no resistance to spinosad, fipronil, indoxacarb, abamectin, Bacillus thuringiensis (Bt) var kurstaki, Bt var aizawai or Cry1Ac when compared with a susceptible laboratory population, Lab-UK. A sub-population was selected for six generations (laboratory G3-G8) with deltamethrin (delta-SEL), while a second sub-population was left unselected (UNSEL). Bioassays at G9 found that selection with deltamethrin gave resistance ratios of >230 compared with UNSEL (>6730 compared with Lab-UK). The delta-selected population showed no apparent cross-resistance to spinosad, fipronil or indoxacarb. Logit regression analysis of F1 reciprocal crosses between delta-SEL and Lab-UK indicated that resistance to deltamethrin in the delta-SEL population was inherited as an autosomal, incompletely dominant (D(LC) = 0.67) trait. A direct test of monogenic inheritance based on a back-cross of F1 progeny with delta-SEL suggested that resistance to deltamethrin was controlled by more than one factor.

Animals↗
PubMed2002

A non-Mendelian inheritance of resistance to strobilurin fungicides in Ustilago maydis.

Mutants of Ustilago maydis (DC) Corda with high resistance to azoxystrobin (RF 164 to 4714, based on EC50 values), an inhibitor of mitochondrial electron transport at the cytochrome bc1 complex, were isolated in a mutation frequency of 2.3 x 10(-7) after nitrosoguanidine mutagenesis and selection on media containing 1 microgram ml-1 azoxystrobin in addition to 0.5 mM salicylhydroxamate (SHAM), a specific inhibitor of cyanide-resistant (alternative) respiration. Oxygen uptake in whole cells was strongly inhibited in the wild-type strains by azoxystrobin (1.5 micrograms ml-1) in addition to SHAM (1 mM), but not in the mutant isolates. Genetic analysis with nine such mutant isolates resulted in progeny phenotypes which did not follow Mendelian segregation, but satisfied the criteria of non-Mendelian (cytoplasmic) heredity. In crosses between three mutant isolates with the compatible wild-type strains, the sensitivity was inherited by progeny maternally from the wild-type parent strain (criterion of uniparental inheritance). In crosses between wild-type strains and remaining mutant isolates, a continuous distribution of sensitivity in the progeny was found (criterion of vegetative segregation). The third criterion of cytoplasmic resistance (criterion of intracellular selection) was fulfilled by experiments on the stability of resistance phenotypes. With two exceptions, a reduction of resistance was observed in the mutant strains when they were grown on inhibitor-free medium. Recovery of the high resistance level was observed after they were returned to the selection medium. Cross-resistance studies with other fungicides, which also inhibit electron transport through complex III of respiratory chain, showed that mutations for resistance to azoxystrobin were also responsible for reduced sensitivity to kresoxim-methyl (RF 18 to 1199) and to antimycin-A (RF 20 to 305), which act at the Qo and Qi sites of the cytochrome bc1 complex, respectively. Studies of the fitness of azoxystrobin-resistant isolates showed that these mutations appeared to be pleiotropic, having significant adverse effects on growth in liquid culture and pathogenicity on young corn plants.

Acrylates↗
PubMed2004

Molecular characterization and inheritance of resistance to ACCase-inhibiting herbicides in Lolium rigidum.

The molecular basis and mode of inheritance of resistance to ACCase-inhibiting herbicides were investigated in a biotype of Lolium rigidum Gaud that has been discovered in Israel. Dose-response experiments at the whole-plant level have revealed that the resistant biotype was more resistant (6.3- to 40-fold) than the susceptible wild-type to ACCase-inhibiting herbicides. A 276-bp genomic DNA encoding the carboxyltransferase domain within the chloroplastic ACCase from resistant and susceptible biotypes were amplified by PCR and analyzed. Sequence comparison revealed that a single isoleucine-to-leucine substitution differentiated ACCases from susceptible and resistant biotypes (corresponds to residue 1769 of wheat ACCase, Acc No AF029895). A PCR amplification of specific alleles (PASA) method was developed to detect the allele composition leading to isoleucine-leucine mutation. ACCase extracted from homozygote resistant, heterozygote and homozygote susceptible plants showed IC50 values of 25.8, 5.6 and 0.6 microM, respectively, suggesting that alteration in the ACCase is governed by a co-dominant gene. The inheritance studies confirmed that the resistance of L rigidum to ACCase-inhibiting herbicides is governed by a single, nuclear and co-dominant gene.

Acetyl-CoA Carboxylase↗
PubMed2005

Ion-pairing reversed-phase liquid chromatography/electrospray ionization mass spectrometric analysis of 76 underivatized amino acids of biological interest: a new tool for the diagnosis of inherited disorders of amino acid metabolism.

Seventy-six molecules of biological interest for the diagnosis of inherited disorders of amino acids (AA) metabolism have previously been demonstrated to be detectable in electrospray ionization tandem mass spectrometry (ESI-MS/MS) positive mode without derivatization. Reversed-phase liquid chromatography (RPLC) separation on different C18 columns using various perfluorinated carboxylic acids as ion-pairing agents has been found suitable for coupling with MS/MS, and for the separation of AA. A new procedure was optimized in order to replace the usual ion-exchange chromatographic, post-column ninhydrin derivatization, time-consuming routine method. This procedure allowed an adequate separation of all the molecules from other known interfering compounds, and a throughput of two samples per hour. Quantification limits for each molecule were found to be compatible with their measurement in plasma and urine. We validated the qualitative part of the method by analyzing plasma and urine samples from patients affected with several inherited disorders of AA metabolism. We validated the quantification of 16 AA using their stable isotopes as internal standard. The calibration curves were linear over the range 0-3 mM. The quantitative results obtained with the new method on 105 plasma and 99 urine samples were in good agreement with those obtained by the established routine method. Spiking experiments and precision results were also satisfactory.

Amino Acid Metabolism, Inborn Errors↗
PubMed1995

A novel mtDNA point mutation in maternally inherited cardiomyopathy.

A novel mtDNA mutation at position nt. 4300 in the tRNAIle gene is associated with hypertrophic cardiomyopathy inherited as a maternal trait. Interestingly, this mutation seems to cause a pure heart disease as opposed to most other mtDNA mutations, which are associated with multisystemic disorders. Hypertrophic cardiomyopathies are genetically heterogeneous, and mtDNA defects should be considered in the differential diagnosis, especially when there is evidence of maternal inheritance.

Adult↗
PubMed2000

Mitochondrial DNA variations in patients with maternally inherited diabetes and deafness syndrome.

Mitochondrial DNA (mtDNA) variants have been implicated in the pathogenesis of diabetes. A mutation in the tRNA leucine gene at position 3243 has been previously reported in mtDNA of maternally inherited diabetes and deafness (MIDD) patients. Because the true prevalence of the mitochondrial origin in diabetes may be underestimated, we searched for potentially diabetogenic anomalies of mtDNA in 9 patients highly suspected of mitochondrial diabetes selected on maternally inheritance and clinical features. In order to detect high levels of mutant DNA, the mtDNA of muscle sample of 2 patients was totally sequenced and the 22 tRNA genes and flanking sequences of 7 patients were analyzed. A new homoplasmic mutation at position 8381 was found in the ATPase 8 gene of mtDNA of a MIDD patient. The prevalence of three homoplasmic variations (G1888A, T4216G, A4917G) was significantly higher in the small group of MIDD patients compared to controls and other subjects groups. This study demonstrated in our patients sample the high frequency of homoplasmic variations, which could play a role by themselves or in combination, in the pathogenesis of diabetes.

Adult↗
PubMedDate not supplied

A new type of inherited catalase deficiencies: its characterization and comparison to the Japanese and Swiss type of acatalasemia.

Thirteen Hungarian families that exhibited inherited catalase deficiencies have been detected. Differences between the deficiencies reported from Hungary and the previously reported Swiss acatalasemia were characterized using biochemical analysis of the catalase proteins. Molecular biological methods were used to compare the previously reported types of catalase deficiencies in Japan and the Hungarian deficiencies. Three mutations (a GA insertion in exon 2, a G insertion in exon 2, and a T to G substitution in intron 7) are responsible for decreased catalase activity in 7 of the 13 Hungarian kindreds; the other 6 families have not yet been characterized. These are not the mutations observed in Japan. Changes in lipid and carbohydrate metabolism and the high incidence (12.7%) of diabetes mellitus in the Hungarian kindreds suggest that individuals with inherited catalase deficiency are at risk of atherosclerosis and diabetes mellitus. The Hungarian subjects were detected during screening of a large population for catalase activity; no overt disease state was associated with the deficiencies. We hypothesize that the increased risk of disease may be due to prolonged exposure to elevated levels of blood hydrogen peroxide due to the lack of normal removal of hydrogen peroxide by blood catalase.

Acatalasia↗
PubMed2002

The frequency of inherited hydrocephalus is influenced by intrauterine factors in H-Tx rats.

H-Tx rats have fetal-onset inherited hydrocephalus. Linkage analysis has determined the genetics is complex, with at least three loci associated with hydrocephalus. In addition, maternal and/or intrauterine factors influence the frequency of expression. The aim of this study was to characterize nongenetic (epigenetic) factors that affect hydrocephalus in this strain. Groups of primiparous and multiparous females were used to breed fetuses for examination in utero. Multiparous females were manipulated to have either gestation with lactation or, by removal of pups at birth, gestation without lactation. In addition, hydrocephalus expression in postnatal rats from the breeding colony was analyzed for primiparous and multiparous females. The latter were subdivided according to the interval between the litter examined and the previous litter. There was no particular uterine position or horn that favored hydrocephalus and hydrocephalic fetuses were the same weight as normal littermates. The frequency of hydrocephalus was 16-20% in primiparous females and twofold higher in multiparous females that were lactating during pregnancy. Removal of the suckling pups prevented this increase. The severity of hydrocephalus was measured on 1-mm-thick fixed brain slices. Fetuses from lactating females had hydrocephalus that was significantly more severe than the nonlactating groups. However, all fetus groups had hydrocephalus that was very much less severe than the postnatal pups, suggesting that severity increases after birth. It is concluded that there is an epigenetic factor that increases the frequency of inherited hydrocephalus in fetuses if suckling pups are present during gestation. Future experiments will examine possible mechanisms for this genotype-environment interaction.

Animals↗
PubMed1997

B-cell deficiency does not abrogate development of cutaneous hyperplasia in mice inheriting the defective fibrillin-1 gene.

Tight-skin (TSK) mouse, the experimental model for scleroderma, develops cutaneous hyperplasia, cardiac hypertrophy, pulmonary emphysema and autoimmunity against scleroderma target autoantigens. The cutaneous hyperplasia is associated with the accumulation of microfibrils and elastic fibers in the middle and deep dermis. Fibrillin-1 (Fbn-1) is a major component of the 10-12 nm microfibrils found in the extracellular matrix. In this study we report the identification of a genetic marker in the Fbn-1 gene that can distinguish the mutant phenotype. TSK mice exhibit an unique polymorphism in the Fbn-1 gene. RNA analysis, PCR analysis and sequence determination of the mutant gene showed that the Fbn-1 gene polymorphism is due to intragenic duplication of a segment of the gene coding for 3.0 Kb of mRNA sequence (10 Kb of the genome). Histological analysis of skin samples from F1 progeny obtained by crossing TSK mice with JH-/-, RAG2-/- or vit/vit showed a significant correlation between the inheritance of the defective Fbn-1 gene and the development of cutaneous hyperplasia. Further, our results also show that in mice deficient in mature B cells inheriting the defective Fbn-1 gene, development of cutaneous hyperplasia is not abrogated. Thus, production of autoantibodies or the presence of mature B lymphocytes do not play an integral role in the pathogenesis of cutaneous hyperplasia.

Amino Acid Sequence↗
PubMed1996

The inheritance of phenotypes: an adaptation to fluctuating environments.

We discuss simple models for the evolution of rates of spontaneous and induced heritable phenotypic variations in a periodically fluctuating environment with a cycle length between two and 100 generations. For the simplest case, the optimal spontaneous transition rate between two states is approximately 1/n (where n is the cycle length). It is also shown that selection for the optimal transition rate under these conditions is surprisingly strong. When n is small, this means that the heritable variations are produced by non-classical inheritance systems, including non-DNA inheritance systems. Thus, it is predicted that in genes controlling adaptation to such environments, non-classical genetic effects are likely to be observed. We argue that the evolution of spontaneous and induced heritable transitions played an important role in the evolution of ontogenies of both unicellular and multicellular organisms. The existence of a machinery for producing induced heritable phenotypic variations introduces a "Lamarckian" factor into evolution.

Adaptation, Physiological↗
PubMed1998

Complex traits and polygenic inheritance in the mouse.

Polygenic inheritance has recently become an increasingly active field of research due to the availability of techniques allowing in-depth screening of genetic markers across the entire genome. The mouse is being used both in its own right and as a model system for certain human traits. The advantages and disadvantages of the mouse for such studies are outlined and in this context, the adequacy of the mouse as a model for polygenic traits in humans is discussed. A detailed overview of the approaches and methods used in the analysis of polygenic inheritance in the mouse is presented.

Animals↗
PubMed1998

Inherited disorders of fatty alcohol metabolism.

The importance of long-chain aliphatic alcohols to human biology has recently been emphasized by the discovery of several inborn errors of fatty alcohol metabolism. These inherited diseases include isolated defects in the oxidation of fatty alcohol to fatty acid (Sjögren-Larsson syndrome) and deficient incorporation of fatty alcohol into ether lipids (isolated alkyl dihydroxyacetone phosphate synthase deficiency). In addition, disorders of peroxisomal biogenesis (Zellweger syndrome, neonatal adrenoleukodystrophy, infantile Refsum disease) and peroxisomal protein import (rhizomelic chondrodysplasia punctata) have impaired ether lipid synthesis along with other associated defects in peroxisomal metabolism. All of the inherited disorders of fatty alcohol metabolism are associated with severe neurologic disease, but the contribution of tissue fatty alcohol accumulation to the pathogenesis is not clear. Molecular genetic studies have recently identified many of the disease-causing mutations in these disorders, which should lead to more accurate diagnosis and genetic counseling. Although prenatal diagnosis offers a method for preventing these genetic diseases, no effective therapy exists to alleviate the symptoms.

Aldehyde Oxidoreductases↗
PubMed1999

Recent developments in the investigation of inherited metabolic disorders using cultured human cells.

Thepurpose of this paper is to share experience with our systems and review recent "in vitro" methods using intact cells (fibroblasts, amniocytes) in which entire metabolic pathways can be probed for inherited metabolic defects reflected by elevations of intermediates determined by tandem mass spectrometry, HPLC, or gas chromatography-mass spectrometry. Currently, one can explore the integrity of mitochondrial fat oxidation, peroxisomal degradation of methyl-branched fatty acids (e.g., pristanate), and the mitochondrial degradation of the branched chain amino acids (leucine, valine, and isoleucine). For many of the diseases, the specific defect can be recognized from the acylcarnitine profile resulting from incubation of the intact cells with stable-isotope-labeled precursors to the particular pathway. This approach has also been successful in identifying new inherited metabolic disorders, biochemical correlation with clinical phenotypes of individual defects, and sequential oxidation of fatty acids by peroxisomal-mitochondrial interaction.

3-Hydroxyacyl CoA Dehydrogenases↗
PubMed2000

A functional lagging strand origin does not stabilize plasmid pMV158 inheritance in Escherichia coli.

Plasmid rolling circle replication generates single-stranded DNA intermediates. The intracellular amount of these molecules depends upon the efficiency of the conversion of single-stranded into double-stranded plasmid forms, that is, the functionality of the lagging strand origin (sso). The broad-host-range streptococcal plasmid pMV158 harbors two different ssos, both of which function efficiently in Streptococcus pneumoniae but poorly in Escherichia coli. Plasmid pMV158 is stably inherited in the pneumococcal host, but it is unstable in E. coli. A pMV158 derivative lacking its two ssos is unstable in both strains. We have cloned into this derivative the coliphage f1 lagging strand origin. Whereas the f1 sso was fully functional in E. coli, it did not show any activity in S. pneumoniae, a bacteria closely related to the pMV158 natural host. The presence of the f1 sso did not stabilize pMV158 inheritance in either the gram-positive or the gram-negative host.

Cloning, Molecular↗