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At least 1,387 records · Page 77Linked to original sources
PubMed2003

Transcriptional regulation of cytochrome P4503A4 gene expression: effects of inherited mutations in the 5'-flanking region.

1. Understanding the genetic basis of interindividual variability in drug disposition and response is a fundamental focus for rational and individualized drug treatment. Cytochrome P4503A4 (CYP3A4) has a central role in human drug metabolism and polymorphic variation has been reported in this gene. 2. This study reports the in vitro functional analysis of inherited mutations in the 5' flanking region of the CYP3A4 gene using reporter constructs in which the 1141 bp proximal promoter region from the mutant alleles was inserted between a single copy of the CYP3A4 300 bp core distal enhancer (XREM) sequence and the cDNA for human secretory alkaline phosphatase. 3. Reporter constructs were co-transfected with an hPXR expression vector into human liver and intestinal cells in culture and xenobiotic modulation of CYP3A4 promoter activity determined by chemiluminescent secretory alkaline phosphatase assay. DNA-protein interactions were next examined using electrophoretic mobility shift assays. 4. The results demonstrated that inherited mutations in the CYP3A4 gene proximal promoter region could cause significant up-regulation of in vitro transcriptional activation by CYP3A4 xenobiotic inducers. In addition, the magnitude of the effect appeared to be dependent on the cell type used in the functional assays, possibly due to the differing availability of specific intracellular transcription factors or their activating ligands.

5' Flanking Region↗
PubMed2005

Length of the cleft in relation to the incidence of hypodontia of the second premolar and to inheritance of cleft lip and palate in children with isolated cleft palate.

We studied severity of the isolated cleft palate expressed as the length of the cleft in relation to hypodontia in the second premolar regions and known inheritance of any type of cleft lip and palate. The material consisted of 47 children at 10 years of age born with non-syndromic isolated cleft palate of varying extent, who all had hypodontia of at least one second premolar, and had panoramic radiographs taken at 10 years of age. Information about length of cleft and inheritance of cleft lip and palate was collected from surgical files initiated at birth. The higher the number of missing second premolars, the more extended was the length of the cleft. More children had hypodontia of the second premolar in the mandible than in the maxilla. The family history had little influence on the length of the cleft.

Anodontia↗
PubMedDate not supplied

Inherited skeletal muscle disorders.

The field of inherited skeletal muscle disease research has advanced rapidly since the identification of mutations in the dystrophin gene as the cause of Duchenne muscular dystrophy in 1987. From that point, an ever-increasing number of the genes associated with inherited muscle diseases have been identified. These discoveries have led to much more accurate diagnosis of the individual diseases and have allowed prenatal diagnosis where this was not previously possible. The major challenges for the future are to understand the pathophysiology of the diseases, now that the genes are being identified, and then to develop successful therapies.

Dystrophin↗
PubMed2006

Inherited hemoglobin disorders in Guinea-Bissau, West Africa: a population study.

The determination of the prevalence of inherited hemoglobin (Hb) disorders in endemic areas is important in order to develop programs for their control and management. The aim of this study is to determine the prevalence of inherited Hb diseases in Guinea-Bissau which is situated on the west coast of Africa, between Senegal and Guinea. One thousand and fifty-seven blood samples were collected and analyzed with high performance liquid chromatography (HPLC) for detection of beta-thalassemia (thal) and Hb variants, and by gap polymerase chain reaction (gap-PCR) for the detection of deletions in the alpha-globin genes. We found 4.7% children were heterozygous for Hb S [beta6(A3)Glu-->Val, GAG -->GTG], 0.2% were homozygous for Hb S, and 0.3% were heterozygous for Hb C [beta6(A3)Glu-->Lys, GAG -->AAG]. One child had heterozygous beta+-thal, 13.8% were heterozygous for the -alpha3.7 deletion, 1.5% were homozygous for the -alpha3.7 deletion, and 1.5% were heterozygous for the -alpha4.2 deletion. We recommend national screening programs to focus primarily on sickle cell disease, since beta-thal is rare, and the observed alpha-thal deletions are of minor genetic importance.

Anemia, Sickle Cell↗
PubMed2006

An inherited macrothrombocytopenic disorder with abnormal large granules.

Inherited giant platelet syndromes are a heterogeneous group of rare bleeding disorders. In the current study, a patient was reported with prolonged bleeding time, thrombocytopenia and giant platelets. Both the patient's red and white cell counts were normal without morphological abnormalities. The electron microscopy of platelets showed abnormal large electron-dense granules in the cytoplasm with exocytosis being easily observed. Her fathers platelets had the same abnormalities. The expression of glycoprotein (GP)Ib, GPIIb and GPIIIa on the surface of the patient's platelets was normal, and her platelet aggregation in response to ADP and ristocetin was also normal. Immunogold probes combined to monoclonal antibodies against GPIIIa, P-selectin or CD63 could not identify any relationship between the aberrant structures and alpha granules or lysosomes of platelet. Serotonin level was normal in the platelets of the patient, indicating the electron opaque granules are not dense bodies. The morphological abnormalities of the platelets from the patient are clearly distinguishable from other hereditary giant platelet disorders. We propose that the abnormal large granules from the patient's platelets probably represent a novel inherited thrombocytopenic disorder.

Adult↗
PubMed2005

Unilateral isolated microphthalmia inherited as an autosomal recessive trait.

PURPOSE: To report a family with unilateral isolated microphthalmia showing an autosomal recessive pattern of inheritance. CASE REPORT: We report a family in which three out of four children, one male and monozygotic female twins, were born with unilateral isolated microphthalmia to healthy consanguineous parents. One twin additionally had a horseshoe kidney. Rare cases of familial isolated microphthalmia/anophthalmia have been previously described. This is the first report of a family with autosomal recessive isolated microphthalmia occurring unilaterally in all affected individuals. It remains unknown how this inherited genetic disease results in unilateral manifestation. CONCLUSION: Mirror imaging of this condition in the monozygotic twins may help elucidate the underlying mechanism. The constellation of features in this family may contribute to solve remaining questions of research into symmetry and asymmetry.

Abnormalities, Multiple↗
PubMed2001

Ironing out disease: inherited disorders of iron homeostasis.

Iron presents us with a paradox. Without it, cells simply cannot survive because iron is an essential cofactor for many enzymes in critical biochemical pathways. However, when iron is present in excess, it can be highly cytotoxic due to its propensity to catalyze the formation of reactive oxygen radicals. To cater for this dual nature, cells and organisms have developed elaborate mechanisms for regulating iron intake and efflux. When these mechanisms are disrupted, as is the case in a number of inherited disorders of iron metabolism, the pathological consequences can be severe. Many of these disorders are characterized by iron overload and include relatively common diseases such as hereditary hemochromatosis, rare abnormalities of plasma protein synthesis (atransferrinemia and aceruloplasminemia), and the neuromuscular disease Friedreich ataxia. The few described inherited anemias in humans have yet to yield to molecular dissection, but the investigation of several rodent anemias has proved highly rewarding. This review will provide a summary of some of these disorders and describe how their analysis has provided important new insights into iron trafficking pathways and their regulation.

Animals↗
PubMed2004

Family and population strategies for screening and counselling of inherited cardiac arrhythmias.

Family screening in inherited cardiac arrhythmias has been performed in The Netherlands since 1996, when diagnostic DNA testing in long QT syndrome (LQTS) and hypertrophic cardiomyopathy (HCM) became technically possible. In multidisciplinary outpatient academic clinics, an adjusted protocol for genetic counselling, originally derived from predictive testing in Huntington's disease, is being used. 1110 individuals, including 842 relatives of index patients, were informed about their risks, and most were tested molecularly and/or clinically for carriership of the disease present in their family. Of 345 relatives who were referred for cardiologic follow-up, 189 are being treated, because of an increased risk of life-threatening arrhythmias. Evaluation of the psychological and social consequences of family screening for inherited arrhythmias can be performed by using the adapted criteria of Wilson and Jüngner, i.e., from a point of view of public health. Preliminary results of psychological research show that parents of children at risk for LQTS show high levels of distress. Many other aspects have to be evaluated yet, making final conclusions about the feasibility of family screening difficult, particularly in HCM. Clinical guidelines are urgently needed. Population screening by molecular testing, for instance in athletic preparticipation screening, will become possible in the future and has its own prerequisites for success.

Arrhythmias, Cardiac↗
PubMed1980

Hereditary genius: a centennial problem in resolution of cultural and biological inheritance.

Galton believed that his data on hereditary genius support purely genetic inheritance. On the contrary, analysis under a simple model shows no clear resolution of genetic and cultural inheritance in this material, or generally, unless adoptive relations, monozygous twins, and/or environmental indices are included in a design adequate to test the assumptions under which they are informative.

Adult↗
PubMedDate not supplied

Race and the inheritance of low birth weight.

This paper uses intergenerational data from the Panel Study of Income Dynamics (PSID) to address the black-white difference in propensities toward low birth weight (LBW). We determine that socioeconomic conditions account for some variation in low birth weight across race. Further, while race differences in the risk of low birth weight cannot be explained entirely, we find that the inheritance of parental birth weight status dramatically reduces the black-white gap in low birth weight. Intergenerational legacies of poor infant health explain the largest share of racial disparities in filial birth weight. We then try to assess whether this intergenerational transmission of low birth weight is indeed genetic by using grandparent-fixed effects models to factor out, to a great extent, family socioeconomic circumstances. We find that even within this framework, both father's and mother's birth weight status have an important impact on filial outcomes. However, the degree of inheritance is weaker for African Americans than for other races. Finally, we theorize that the importance of paternal birth weight status implies a genetic association that does not work through the uterine environment but rather through the fetus itself.

Adolescent↗
PubMed2005

Genetic testing for inherited breast cancer risk in African Americans.

As genetic testing for BRCA1 and BRCA2 (BRCA1/2) mutations is increasingly integrated into the clinical management of high-risk women, it will be important to understand barriers and motivations for genetic counseling among women from underserved minority groups to ensure equitable access to these services. Therefore, the purpose of this review was to synthesize literature on knowledge and attitudes about genetic counseling and testing for inherited breast cancer risk in African Americans. We also review studies that evaluated genetic testing intentions in this population. We conducted a search of the PubMed database to identify studies related to BRCA1/2 testing in African Americans that were published between 1995 and 2003. Overall, studies have evaluated ethnic differences in knowledge and attitudes about genetic testing or have compared African American and Caucasian women in terms of genetic testing intentions. These studies have shown that knowledge about breast cancer genetics and exposure to information about the availability of testing is low among African Americans, whereas expectations about the benefits of genetic testing are endorsed highly. However, much less is known about the psychological and behavioral impact of genetic testing for BRCA1/2 mutations in African Americans. Additional research is needed to understand barriers and motivations for participating in genetic testing for inherited cancer risk in African Americans. The lack of studies on psychological functioning, cancer surveillance, and preventive behaviors following testing is a significant void; however, for these studies to be conducted, greater access to genetic counseling and testing in African Americans will be needed.

Black People↗
PubMed1994

G-protein ligands inhibit in vitro reactions of vacuole inheritance.

During budding in Saccharomyces cerevisiae, maternal vacuole material is delivered into the growing daughter cell via tubular or vesicular structures. One of the late steps in vacuole inheritance is the fusion in the bud of vesicles derived from the maternal vacuole. This process has been reconstituted in vitro and requires isolated vacuoles, a physiological temperature, cytosolic factors, and ATP (Conradt, B., J. Shaw, T. Vida, S. Emr, and W. Wickner. 1992. J. Cell Biol. 119:1469-1479). We now report a simple and reliable assay to quantify vacuole-to-vacuole fusion in vitro. This assay is based on the maturation and activation of vacuole membrane-bound pro-alkaline phosphatase by vacuolar proteinase A after vacuole-to-vacuole fusion. In vitro fusion allowed maturation of 30 to 60% of pro-alkaline phosphatase. Vacuoles prepared from a mutant defective in vacuole inheritance in vivo (vac2-1) were inactive in this assay. Vacuole fusion in vitro required a vacuole membrane potential. Inhibition by nonhydrolyzable guanosine derivatives, mastoparans, and benzalkonium chloride suggest that GTP-hydrolyzing G proteins may play a key role in the in vitro fusion events.

Amino Acid Sequence↗
PubMed1994

Regulation of mitochondrial morphology and inheritance by Mdm10p, a protein of the mitochondrial outer membrane.

Yeast cells with the mdm10 mutation possess giant spherical mitochondria and are defective for mitochondrial inheritance. The giant mitochondria display classical features of mitochondrial ultrastructure, yet they appear incapable of movement or division. Genetic analysis indicated that the mutant phenotypes resulted from a single nuclear mutation, and the isolated MDM10 gene restored wild-type mitochondrial distribution and morphology when introduced into mutant cells. MDM10 encodes a protein of 56.2 kD located in the mitochondrial outer membrane. Depletion of Mdm10p from cells led to a condensation of normally extended, tubular mitochondria into giant spheres, and reexpression of the protein resulted in a rapid restoration of normal mitochondrial morphology. These results demonstrate that Mdm10p can control mitochondrial morphology, and that it plays a role in the inheritance of mitochondria.

Amino Acid Sequence↗
PubMed1997

A heterodimer of thioredoxin and I(B)2 cooperates with Sec18p (NSF) to promote yeast vacuole inheritance.

Early in S phase, the vacuole (lysosome) of Saccharomyces cerevisiae projects a stream of vesicles and membranous tubules into the bud where they fuse and establish the daughter vacuole. This inheritance reaction can be studied in vitro with isolated vacuoles. Rapid and efficient homotypic fusion between salt-washed vacuoles requires the addition of only two purified soluble proteins, Sec18p (NSF) and LMA1, a novel heterodimer with a thioredoxin subunit. We now report the identity of the second subunit of LMA1 as I(B)2, a previously identified cytosolic inhibitor of vacuolar proteinase B. Both subunits are needed for efficient vacuole inheritance in vivo and for the LMA1 activity in cell extracts. Each subunit acts via a novel mechanism, as the thioredoxin subunit is not acting through redox chemistry and LMA1 is still needed for the fusion of vacuoles which do not contain proteinase B. Both Sec18p and LMA1 act at an early stage of the in vitro reaction. Though LMA1 does not stimulate Sec18p-mediated Sec17p release, LMA1 cannot fulfill its function before Sec18p. Upon Sec17p/Sec18p action, vacuoles become labile but are rapidly stabilized by LMA1. The action of LMA1 and Sec18p is thus coupled and ordered. These data establish LMA1 as a novel factor in trafficking of yeast vacuoles.

Adenosine Triphosphatases↗
PubMed1998

An ordered inheritance strategy for the Golgi apparatus: visualization of mitotic disassembly reveals a role for the mitotic spindle.

During mitosis, the ribbon of the Golgi apparatus is transformed into dispersed tubulo-vesicular membranes, proposed to facilitate stochastic inheritance of this low copy number organelle at cytokinesis. Here, we have analyzed the mitotic disassembly of the Golgi apparatus in living cells and provide evidence that inheritance is accomplished through an ordered partitioning mechanism. Using a Sar1p dominant inhibitor of cargo exit from the endoplasmic reticulum (ER), we found that the disassembly of the Golgi observed during mitosis or microtubule disruption did not appear to involve retrograde transport of Golgi residents to the ER and subsequent reorganization of Golgi membrane fragments at ER exit sites, as has been suggested. Instead, direct visualization of a green fluorescent protein (GFP)-tagged Golgi resident through mitosis showed that the Golgi ribbon slowly reorganized into 1-3-micron fragments during G2/early prophase. A second stage of fragmentation occurred coincident with nuclear envelope breakdown and was accompanied by the bulk of mitotic Golgi redistribution. By metaphase, mitotic Golgi dynamics appeared to cease. Surprisingly, the disassembly of mitotic Golgi fragments was not a random event, but involved the reorganization of mitotic Golgi by microtubules, suggesting that analogous to chromosomes, the Golgi apparatus uses the mitotic spindle to ensure more accurate partitioning during cytokinesis.

Animals↗
PubMed2003

Myo4p and She3p are required for cortical ER inheritance in Saccharomyces cerevisiae.

Myo4p is a nonessential type V myosin required for the bud tip localization of ASH1 and IST2 mRNA. These mRNAs associate with Myo4p via the She2p and She3p proteins. She3p is an adaptor protein that links Myo4p to its cargo. She2p binds to ASH1 and IST2 mRNA, while She3p binds to both She2p and Myo4p. Here we show that Myo4p and She3p, but not She2p, are required for the inheritance of cortical ER in the budding yeast Saccharomyces cerevisiae. Consistent with this observation, we find that cortical ER inheritance is independent of mRNA transport. Cortical ER is a dynamic network that forms cytoplasmic tubular connections to the nuclear envelope. ER tubules failed to grow when actin polymerization was blocked with the drug latrunculin A (Lat-A). Additionally, a reduction in the number of cytoplasmic ER tubules was observed in Lat-A-treated and myo4Delta cells. Our results suggest that Myo4p and She3p facilitate the growth and orientation of ER tubules.

Actin Cytoskeleton↗
PubMed1964

DISTRIBUTION, INHERITANCE, AND PROPERTIES OF AN ANTIGEN, MUB1, AND ITS RELATION TO HEMOLYTIC COMPLEMENT.

An antigen, MuB1, present in the sera of some mice, can elicit a precipitating antibody in certain other strains of mice. An antibody to the antigen MuB1 can also be elicited in rabbits. 99 strains and substrains of inbred mice were tested for the presence of MuB1; the antigen was found in the sera of 44 strains (61 per cent) and 14 DBA substrains (52 per cent). Evidence is presented indicating that mice lacking MuB1 do not make a modified antigen, corresponding to MuB1, but are genetically deficient in synthetic ability at this site. By reaction with antibody to MuB1 an antigen corresponding to MuB1 was found in 13 of the 15 orders of mammals, and in 63 of 85 mammalian species tested, including man and guinea pig. The quantity of the antigen MuB1 is always greater in the serum of male than in the serum of female mice. The concentration of MuB1 increases with age; this increase is more marked in male than in female mice. By means of backcross experiments it was shown that the inheritance of MuB1 is unifactorial, is independent of the inheritance of the gamma globulin allotype MuA2, and is qualitatively independent of the sex of the parents. The antigen MuB1 is found in the euglobulin fraction of serum; it loses its ability to precipitate with antibody after heating at 56 degrees C, but not after treatment with ammonia or hydrazine. By gel filtration, MuB1 is separated with a fraction containing molecules of molecular weight approximately 150,000. An empirical correlation was observed between the presence or absence of MuB1 in the sera from inbred mice and the presence or absence of hemolytic complement (Hc), as measured by a test using a high concentration of rabbit hemolysin. In backcross experiments also, a correlation between hemolytic complement and the presence of MuB1 was demonstrated. As with MuB1, male mice had a higher hemolytic complement level than females. The particular component of complement which may be identical with MuB1 has not been identified.

Animals↗
PubMed1966

An inherited X-linked serum system in man; the Xm system.

The detection of an inherited X-linked serum system in man, disclosed by a heteroantisenim made specific by absorption, is described. These studies suggest that the antigen, demonstrated by the specific antiserum, resides in the alpha(2)-macroglobulin fraction of serum. The system has been named the Xm system, where X refers to the localization of the gene on the X chromosome, and the m indicates that the antigen is part of the alpha(2)-macroglobulin fraction. The distribution of phenotypes in unrelated individuals from 4 populations, as well as studies performed in families are consistent with an X-linked dominant mode of inheritance. One Xm(a-) daughter was found in a family where the father was Xm(a+). This finding is discussed with particular reference to the possible influence of sex and age on the development of the phenotype. This common X-linked marker is likely to prove useful in mapping the human X chromosome.

Black or African American↗