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PubMed1996

Inheritance of acetohexamide reductase activities in liver microsomes and cytosol of rats.

The inheritance patterns of acetohexamide reductase activities in liver microsomes and cytosol of rats were determined by using the inbred Wistar-Imamichi and Fischer-344 strains as a model of low and high metabolizers, respectively. A simple Mendelian genetic analysis for the frequency distribution of acetohexamide reductase activity in liver microsomes of male rats led us to conclude that the phenotype is genetically regulated by an autosomal co-dominant fashion. Female rats, unlike male rats, did not exhibit microsomal enzyme activity in parental, first filial (F1) and second filial (F2) generations, indicating that the inheritance of the microsomal enzyme activity is sex-limited. On the other hand, the frequency distribution of acetohexamide reductase activities in liver cytosol of male and female rats was unimodal in all generations and there was no significant difference among these cytosolic enzyme activities.

Alcohol Oxidoreductases↗

PubMed2002

Induction of stem cell cycling in mice increases their sensitivity to a chemical leukaemogen: implications for inherited genomic instability and the bystander effect.

Preconception paternal irradiation (PPI) modifies haemopoietic and stromal tissues of offspring and increases risk of generating lympho-haemopopietic malignancy if those offspring are then exposed to a leukaemogen. We hypothesised that this increased risk was related to inherited damage which had caused increased stem cell proliferation rates. To test for this link, in vivo, rapid stem cell proliferation was established by giving sub-lethal irradiation (3Gy gamma-rays) and allowing 3 days recovery. At this stage, 60% of haemopoietic spleen colony-forming units (CFU-S) were in DNA-synthesis, compared to <10% in unirradiated controls. Two groups of mice, unirradiated controls and irradiated animals, were then injected with 50mg/kg methyl nitrosourea (MNU) and observed daily for onset of lympho-haemopoietic malignancy. In a further control group of 60 mice, irradiated but not injected with MNU, only one leukaemia developed. In unirradiated controls, 20% of the mice developed malignancies between 3 and 8 months later: in the irradiated, MNU-treated groups, 95% developed malignancies between 2 and 7 months later. Thus, at least one powerful potentiating mechanism for induction of lympho-haemopoietc malignancy following inherited damage can be related to haemopoietic stem cell proliferation. Genomic instability is exposed by cell proliferation and has been implicated in this type of damage. However, a regulatory stromal microenvironment plays a part in inducing that proliferation. Thus, the microenvironment is the effective "bystander" which is thought to promote and amplify genomic instability, and thereby influence the induction of malignancy both in PPI offspring and in mice with induced stem cell proliferation.

Alkylating Agents↗

PubMed2001

von Willebrand disease and other inherited bleeding disorders in women with diagnosed menorrhagia.

OBJECTIVE: To estimate the prevalence of von Willebrand disease and other bleeding disorders in women with and without diagnosed menorrhagia. METHODS: Women with menorrhagia were identified among members of a health maintenance organization in the southeastern United States through a computer search for appropriate International Classification of Diseases, 9th Revision codes. A random sample of members with no such code was selected as controls. The study included 121 women with menorrhagia and 123 controls. Subjects were interviewed in person, and blood was drawn for coagulation testing. Laboratory results for menorrhagia patients were compared with those in controls using race and blood type specific ranges developed from the control group. A test was considered abnormal if it exceeded two standard deviations below the control mean. RESULTS: Bleeding disorders (von Willebrand disease, factor deficiency, or a platelet abnormality) were diagnosed in 10.7% of menorrhagia patients and 3.2% of controls (P =.02). von Willebrand disease was present in eight menorrhagia patients (6.6%) and in one control (0.8%) (P =.02); separate analyses by race revealed a von Willebrand disease prevalence of 15.9% among white and 1.4% among black menorrhagia patients (P =.01). Women with bleeding disorders did not differ significantly from controls in other symptoms of bleeding. CONCLUSION: The prevalence of inherited bleeding disorders among white women with menorrhagia was substantial, consistent with European data published recently. For unknown reasons, the prevalence of von Willebrand disease was lower among black women. These findings indicate the importance of considering inherited bleeding disorders as a cause of menorrhagia.

Adolescent↗

PubMed2002

Inherited thrombophilias in pregnant patients: detection and treatment paradigm.

Inherited thrombophilias are the leading cause of maternal thromboembolism and are associated with an increased risk of certain adverse pregnancy outcomes including second- and third-trimester fetal loss, abruptions, severe intrauterine growth restriction, and early-onset, severe preeclampsia. Current information suggests that all patients with a history of prior venous thrombotic events and those with these characteristic adverse pregnancy events should be evaluated for thrombophilias. The most common, clinically significant, inherited thrombophilias are heterozygosity for the factor V Leiden and prothrombin G20210A mutations. The autosomal-dominant deficiencies of protein C and protein S are of comparable thrombogenic potential but are far less common. Homozygosity for the 4G/4G mutation in the type-1 plasminogen activator inhibitor gene and the thermolabile variant of the methylenetetrahydrofolate reductase gene, the leading cause of hyperhomocysteinemia, although relatively common, confer a low risk of thrombosis. In contrast, autosomal-dominant antithrombin deficiency and homozygosity or compound heterozygosity (ie, carriers of one copy of each mutant allele) for the factor V and prothrombin mutations are very rare but highly thrombogenic states. Regardless of their antecedent histories, pregnant patients with these highly thrombogenic conditions are at very high risk for both thromboembolism and characteristic adverse pregnancy outcomes, require full therapeutic heparin therapy throughout pregnancy, and need at least 6 weeks of postpartum oral anticoagulation. There is also compelling evidence that patients with the less thrombogenic thrombophilias and a history of venous thrombotic events or characteristic adverse pregnancy outcomes require prophylactic anticoagulant therapy during pregnancy and, in the case of prior thromboembolism, during the puerperium. Antepartum anticoagulation does not appear warranted among patients with less thrombogenic thrombophilias who are without a history of venous thromboembolism, characteristic adverse pregnancy outcomes, or other high risk factors for venous thrombosis.

Factor V↗

PubMed1990

Congenital heart disease: incidence and inheritance.

Congenital heart disease occurs in approximately 1 per cent of liveborn children, but in a much higher percentage of those aborted spontaneously or stillborn. To detect as many as possible with CHD, including those with mild lesions, very intensive studies are needed. Studies that are not so intensive, especially those done before modern diagnostic techniques were in general use, considerably underestimated the incidence of CHD in liveborn children. It appears that the incidence of CHD and of the various individual lesions does not differ in different countries or at different times, providing the ascertainment of CHD is complete and accurate. The commonest form of CHD is the ventricular septal defect, which occurs in 30 to 40 per cent of all children with CHD. The risks of recurrence in siblings and of transmission to future generations depends on the exact mode of inheritance involved. Approximately 5 to 8 per cent of CHD is due to gross chromosomal abnormalities, and the recurrence risk is that of the chromosomal derangement itself. Because many children with these chromosomal lesions die in infancy or have reduced fertility, the risk to future generations is relatively low. About 3 per cent of CHD is due to classical Mendelian gene effects, with correspondingly high recurrence risks in first-degree relatives. Most CHD has lower risks of recurrence and transmission than those predicted by Mendelian single-gene action. The popular explanation for their inheritance has been the interaction of polygenic effects and the environment, but recent studies of the recurrence and transmission risks of various forms of CHD do not fit this model well. The alternative model is a single gene defect modulated by random events. The recurrence risks for future siblings are 2 to 6 per cent, and for offspring are 1 to 10 per cent, but in a few families the recurrence and transmission risks may be much higher.

Chromosome Aberrations↗

PubMed2001

Recent advances in the molecular basis of inherited skin diseases.

Over the last few years the molecular basis of several inherited skin diseases has been delineated. Some discoveries have stemmed from a candidate gene approach using clinical, biochemical, immunohistochemical, and ultrastructural clues, while others have arisen from genetic linkage and positional cloning analyses. Notable advances have included elucidation of specific gene pathology in the major forms of inherited skin fragility, ichthyosis, and keratoderma. These findings have led to a better understanding of the significance of individual structural proteins and regulatory enzymes in keratinocyte adhesion and differentiation. From a clinical perspective, the advances have led to better genetic counseling in many disorders, the development of DNA-based prenatal diagnosis, and a foundation for planning newer forms of treatment, including somatic gene therapy, in selected conditions.

Epidermis↗

PubMed2005

Nuclear envelope, nuclear lamina, and inherited disease.

The nuclear envelope is composed of the nuclear membranes, nuclear lamina, and nuclear pore complexes. In recent years, mutations in nuclear-envelope proteins have been shown to cause a surprisingly wide array of inherited diseases. While the mutant proteins are generally expressed in most or all differentiated somatic cells, many mutations cause fairly tissue-specific disorders. Perhaps the most dramatic case is that of mutations in A-type lamins, intermediate filament proteins associated with the inner nuclear membrane. Different mutations in the same lamin proteins have been shown to cause striated muscle diseases, partial lipodystrophy syndromes, a peripheral neuropathy, and disorders with features of severe premature aging. In this review, we summarize fundamental aspects of nuclear envelope structure and function, the inherited diseases caused by mutations in lamins and other nuclear envelope proteins, and possible pathogenic mechanisms.

Animals↗

PubMed2006

Role of peripherin/rds in vertebrate photoreceptor architecture and inherited retinal degenerations.

The vertebrate photoreceptor outer segment (OS) is a highly structured and dynamic organelle specialized to transduce light signals. The elaborate membranous architecture of the OS requires peripherin/rds (P/rds), an integral membrane protein and tetraspanin protein family member. Gene-level defects in P/rds cause a broad variety of late-onset progressive retinal degenerations in humans and dysmorphic photoreceptors in murine and Xenopus models. Although proposed to fulfill numerous roles related to OS structural stability and renewal, P/rds molecular function remains uncertain. An increasingly resolved model of this protein's oligomeric structure can account for disease inheritance patterns and severity in some instances. Nonetheless, the pathogenic mechanisms underlying the uniquely broad spectrum of retinal diseases associated with P/rds defects are not currently well understood. Recent findings point to the possibility that P/rds acts as a multifunctional scaffolding protein for OS architecture and that partial-loss-of-function mutations contribute to the hallmark phenotypic heterogeneity associated with inherited defects in RDS.

Amino Acid Sequence↗

PubMed1999

Replication-dependent marking of DNA by PCNA facilitates CAF-1-coupled inheritance of chromatin.

Chromatin assembly factor 1 (CAF-1) is required for inheritance of epigenetically determined chromosomal states in vivo and promotes assembly of chromatin during DNA replication in vitro. Herein, we demonstrate that after DNA replication, replicated, but not unreplicated, DNA is also competent for CAF-1-dependent chromatin assembly. The proliferating cell nuclear antigen (PCNA), a DNA polymerase clamp, is a component of the replication-dependent marking of DNA for chromatin assembly. The clamp loader, replication factor C (RFC), can reverse this mark by unloading PCNA from the replicated DNA. PCNA binds directly to p150, the largest subunit of CAF-1, and the two proteins colocalize at sites of DNA replication in cells. We suggest that PCNA and CAF-1 connect DNA replication to chromatin assembly and the inheritance of epigenetic chromosome states.

Adenosine Triphosphate↗

PubMed1976

Inheritance in protoporphyria. Comparison of haem synthetase activity in skin fibroblasts with clinical features.

The activity of haem synthetase, the enzyme which chelates iron to protoporphyrin to form haem, was measured in cultured skin fibroblasts of children with protoporphyria and their parents from three families. In each family, one parent had deficient haem synthetase activity (3-0-11-1 pmol protohaem formed/mg protein/h) when compared to values in eight non-porphyric controls (means 24-9, range 13-7-51-5). The level of activity in the three parents was similar to that in their affected children. In two families the parent with deficient activity was also thought to be the carrier of the abnormal gene, as judged from a history of photosensitivity and analysis of erythrocyte protoporphyrin concentrations, but in the third family the pattern of inheritance could not be determined from these criteria. The activity of delta-aminolaevulinic acid synthetase was normal in cultured fibroblasts from the protoporphyric children and their parents, excluding a generalised defect in haem-pathway enzymes. These results support the premise that deficient haem synthetase activity, inherited in an autosomal dominant patter, is the primary defect in protoporphyria.

Adolescent↗

PubMed1998

Connexin-26 mutations in sporadic and inherited sensorineural deafness.

BACKGROUND: Hearing impairment affects one infant in 1000 and 4% of people aged younger than 45 years. Congenital deafness is inherited or apparently sporadic. We have shown previously that DFNB1 on chromosome 13 is a major locus for recessive deafness in about 80% of Mediterranean families and that the connexin-26 gene gap junction protein beta2 (GJB2) is mutated in DFNB1 families. We investigated mutations in the GJB2 gene in familial and sporadic cases of deafness. METHODS: We obtained DNA samples from 82 families from Italy and Spain with recessive non-syndromic deafness and from 54 unrelated participants with apparently sporadic congenital deafness. We analysed the coding region of the GJB2 gene for mutations. We also tested 280 unrelated people from the general populations of Italy and Spain for the frameshift mutation 35delG. FINDINGS: 49% of participants with recessive deafness and 37% of sporadic cases had mutations in the GJB2 gene. The 35delG mutation accounted for 85% of GJB2 mutations, six other mutations accounted for 6% of alleles, and no changes in the coding region of GJB2 were detected in 9% of DFNB1 alleles. The carrier frequency of mutation 35delG among people from the general population was one in 31 (95% CI one in 19 to one in 87). INTERPRETATION: Mutations in the GJB2 gene are a major cause of inherited and apparently sporadic congenital deafness. Mutation 35delG is the most common mutation for sensorineural deafness. Identification of 35delG and other mutations in the GJB2 gene should facilitate diagnosis and counselling for the most common genetic form of deafness.

Chromosomes, Human, Pair 13↗

PubMed1985

Progressive inherited retinal arteriolar tortuosity with spontaneous retinal hemorrhages.

Tortuosity of the retinal arterioles complicated by spontaneous retinal hemorrhages is inherited as an autosomal dominant trait. Even when hemorrhages involve the fovea, spontaneous clearing with recovery of normal vision is the rule. We have studied members of three families in which arteriolar tortuosity increases with age. Tortuosity increases most dramatically during adolescence and affects small arterioles in the macular area. Retinal hemorrhages in children from two pedigrees led to extensive laboratory investigation because arteriolar tortuosity, later unmistakeable, was not recognized initially. Inherited retinal arteriolar tortuosity may be overlooked easily, particularly in children. Patients with spontaneous retinal hemorrhages and their relatives should be examined for retinal arteriolar tortuosity before being subjected to cardiovascular or hematologic studies.

Adolescent↗

PubMed1992

Dominantly inherited cystoid macular edema. A histopathologic study.

BACKGROUND: Dominantly inherited cystoid macular edema was described as a clinically distinct form of macular dystrophy with an onset at approximately age 30 years with slow progression over the ensuing decades. This is the first report of the light and electron microscopic findings in two donor eyes of one of the patients with this clinical entity. METHODS: Both eyes were obtained after death and fixed within 24 hours in a buffered 4% formaldehyde-1% glutaraldehyde solution. For light microscopy, tissue was embedded in paraffin and stained with hematoxylin-eosin, periodic acid-Schiff, colloidal iron for mucopolysaccharides, and an antibody to glial fibrillar acidic protein. For ultrastructural investigation, several blocks of choroidal/retinal tissues from the posterior pole, including both maculae, were embedded in epoxy resin and processed for transmission electron microscopy. RESULTS: Major findings included large retinal cysts in the macula, atrophy and marked disorganization of the inner nuclear layer, advanced degeneration of Müller cells with nodular aggregates of basement membrane-like material, and a preretinal membrane. The retinal vasculature did not show excessive endothelial alterations but was surrounded by deposits of multilayered basement membrane in the perivascular space. CONCLUSION: The authors believe that the pathologic features of dominantly inherited cystoid macular edema are different from those of macular edema caused by other disease processes. The predominant pathologic changes affected mainly the inner nuclear layer. The possibility of a primary disease of the Müller cell is suggested.

Aged↗

PubMedDate not supplied

Cell imaging and morphology: application to studies of inherited purine metabolic disorders.

A number of inherited or drug-induced metabolic disorders involving dysfunctions in purines and pyrimidines are strongly associated with neurological dysfunction, e.g., Lesch Nyhan syndrome. Such disorders have been studied extensively using biochemical and molecular techniques in order to examine how such defects occur, sometimes using in vitro models based upon cultured neuroblastoma cell lines. However, these metabolic dysfunctions may manifest their effects in other ways, such as impaired synaptic transmission and gross abnormalities in neuronal growth and differentiation. This review outlines the latter novel facet of purine research. It is proposed that by employing cell imaging techniques and cultured neuroblastoma cell lines, believed to model the nervous system, significant insights into how inherited disorders of purine metabolism affect neuronal development can be obtained. This review provides an example of the application of these techniques to understand the etiology of Lesch Nyhan syndrome, and encourages further study of the role of purines and pyrimidines in the development of the nervous system.

Animals↗

PubMed1996

Inheritance of serum autoantibody, reduced serum IgA and autoimmune disease in a canine breeding colony.

Immunological parameters were examined in 113 English cocker spaniel dogs from two breeding kennels. Dogs from kennel 1 (n = 86) were grouped as having idiopathic cardiomyopathy (n = 19), autoimmune or other disease (n = 7) or being clinically normal (n = 60). Dogs from kennel 2 (n = 27) were all clinically normal and used for comparative purposes. There was a high incidence of serum antinuclear antibody (ANA) amongst all groups from kennel 1 (39/82 dogs tested), with anti-thyroglobulin and anti-erythrocyte antibodies also recorded in a dog with systemic lupus erythematosus. Thirty percent of dogs with idiopathic cardiomyopathy had anti-mitochondrial antibody. Thirteen dogs from kennel 1 had reduced serum IgA (< or = 0.3 mg/ml), but there was no consistent abnormality in the concentration of serum IgG, IgM, complement C3 or C4 in these thirteen dogs, or other dogs from this kennel. No immunological abnormality was recorded in dogs from kennel 2. Pedigree analysis of dogs from kennel 1 revealed inheritance of autoimmune disease, serum ANA and low serum IgA within several breeding lines. Inheritance of idiopathic cardiomyopathy was recorded through three generations and a strong association demonstrated between the presence of this disorder and a particular complement C4 phenotype (C4: 4).

Animals↗

PubMed2000

Genome analysis of collagen disease in MRL/lpr mice: polygenic inheritance resulting in the complex pathological manifestations.

MRL/MpJ-lpr/lpr (MRL/lpr) mice develop collagen disease involving vasculitis, glomerulonephritis, arthritis and sialoadenitis, each of which has been studied as a model for polyarteritis, lupus nephritis, rheumatoid arthritis and Sjögren's syndrome, respectively. In the previous studies, we observed genetic segregation of these complex pathological manifestations throughout the genome recombination with a C57Bl/6-lpr/lpr or a C3H/HeJ-lpr/lpr (C3H/lpr) strain of mice which rarely develops such lesions, indicating that development of collagen disease is dependent on an MRL host genetic background. To clarify the mode of inheritance and the gene loci affecting four types of the lesions in MRL/lpr mice; vasculitis, glomerulonephritis, arthritis and sialoadenitis, a genetic dissection of the lesions was carried out by using MRL/lpr, C3H/lpr, (MRL/lprxC3H/lpr) F1 intercross, and MRL/lprx(MRL/lprxC3H/lpr) F1 backcross mice. Definition of each lesion was performed by histopathology under light microscopy, and genomic DNA of the backcross mice were subjected to association studies by chi-square analysis for determining which polymorphic microsatellite locus occurs at higher frequency among affected compared to unaffected individuals for each lesion. We observed that gene loci recessively associated with each lesion were mapped on different chromosomal positions. We conclude that each of four types of the lesions in MRL/lpr mice is under the control of different set of genes, suggesting the complex pathological manifestations of collagen disease result from polygenic inheritance.

Animals↗

PubMed2000

Both self and non-inherited maternal HLA antigens influence the immune response.

Recent studies suggest that exposure of the fetus and newborn to non-inherited maternal major histocompatibility complex HLA antigens (NIMA) has a life-long effect on allograft recognition that could influence tolerance of organ grafts. NIMA also appear to influence disease susceptibility. Here, Jon van Rood and Frans Claas discuss evidence that three HLA haplotypes, those inherited from the parents plus NIMA, shape the immune response.

Age Factors↗

PubMed2000

The inherited nature of lung cancer: a pilot study.

The role of both primary and secondary cigarette smoke exposure in the causation of lung cancer appears certain. An estimated 90% of lung cancer is attributed to cigarette smoke. Remarkably, however, less then 20% of cigarette smokers develop lung cancer. Investigators have suggested that a genetic predisposition to lung cancer may contribute to familial aggregation of this cancer. To understand the contribution of familial aggregation to this type of cancer and potentially identify individuals and families, which may be important in identifying gene(s) responsible for lung cancer, we developed criteria for identification of high-risk families. We have tested the feasibility and utility of these criteria at three Denver, CO hospitals with very different patient populations. Four hundred eighteen individuals were diagnosed with lung cancer at these three hospitals between 1/1/95 and 8/31/95. Twenty-nine percent of individuals expired prior to the time of initial contact. Family history data were obtained on 182 individuals. To be considered positive (suggesting possible autosomal dominant inheritance of lung cancer), families must have at least two first-degree relatives with lung cancer, one of which must be diagnosed before the age of 55. Seventeen of 182 (9.3%) families in the study population met these criteria. We reviewed the remaining family histories that did not meet the established criteria and identified another 2.3% (5/182) of families had evidence for autosomal dominant transmission of lung cancer. An additional 15% (23/182) of families had histories which could not be classified without further information. This study suggests that at least 11.6% of individuals diagnosed with lung cancer will have a positive family history of lung cancer. Use of the criteria developed for this study may lead to an underestimation of the inherited etiology of lung cancer.

Adult↗