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At least 235 records · Page 13Linked to original sources
PubMed1987

alpha 2-Antiplasmin Enschede: dysfunctional alpha 2-antiplasmin molecule associated with an autosomal recessive hemorrhagic disorder.

alpha 2-Antiplasmin (alpha 2-AP) is a major fibrinolysis inhibitor, whose complete, congenital absence has been found to be associated with a distinct hemorrhagic diathesis. We studied a 15-yr-old male with a hemorrhagic diathesis after trauma from early childhood on. This bleeding tendency was associated with a minimal alpha 2-AP level recorded functionally in the immediate plasmin inhibition test: less than or equal to 4% of normal. However, a normal plasma concentration of alpha 2-AP antigen (83%) was found. His sister (5 yr old) showed similar results (2 and 92%). In their family, eight heterozygotes could be identified by half-normal activity results and normal antigen concentrations. The inheritance pattern is autosomal recessive. On analysis, the alpha 2-AP of the propositus was homogeneous in all respects tested, suggesting a homozygous defect. We designated the abnormal alpha 2-AP as alpha 2-AP Enschede. alpha 2-AP Enschede showed the following characteristics: (a) complete immunological identity with normal alpha 2-AP; (b) normal molecular weight (sodium dodecyl sulfate-polyacrylamide gel electrophoresis); (c) normal alpha-electrophoretic mobility; (d) presence in plasma of both molecular forms excluding an excessive conversion to the less reactive non-plasminogen-binding form; (e) quantitatively normal binding to lys-plasminogen and to immobilized plasminogen kringle 1-3; and (f) normal Factor XIII-mediated binding to fibrin. Functional abnormalities were found in: (i) no inhibition of amidolytic activities of plasmin and trypsin, even on prolonged incubation; (ii) no formation of plasmin-antiplasmin complexes in plasma with plasmin added in excess; and (iii) no inhibition of fibrinolysis by fibrin-bound alpha 2-AP. In the heterozygotes, the presence of abnormal alpha 2-AP did not interfere with several functions of the residual normal alpha 2-AP. One-dimensional peptide mapping showed an abnormal pattern of papain digestion. We conclude that in this family, abnormal antiplasmin molecules, defective in plasmin inhibition but with normal plasminogen-binding properties, have been inherited. The residual plasminogen-binding properties do not protect against a hemorrhagic diathesis.

Adolescent↗
PubMed2025

A pathogenic COL7A1 variant highlights semi-dominant inheritance in dystrophic epidermolysis bullosa.

Dystrophic epidermolysis bullosa is a rare subtype of inherited epidermolysis bullosa, caused by variants in the collagen type VII alpha 1 chain (COL7A1) gene (MIM120120). Both autosomal dominant and recessive inheritance has been reported with variable phenotype. We investigated a Pakistani family with dystrophic epidermolysis bullosa via exome sequencing and identified a pathogenic nonsense variant in COL7A1 NM_000094 c.1573 C > T:p.(Arg525*). The inheritance pattern observed was consistent with a semi-dominant model, where heterozygous parents exhibited a mild phenotype, and homozygous children were more severely affected. For dystrophic epidermolysis bullosa, loss-of-function variants are typically associated with the autosomal recessive form, while missense variants are linked to the autosomal dominant form. A review of the literature suggests a semi-dominance pattern for some missense variants, particularly glycine substitutions, but this concept had not been formally recognized. This study highlights the importance of considering semi-dominant inheritance models for dystrophic epidermolysis bullosa and other Mendelian diseases with an autosomal recessive mode of inheritance, as it can significantly impact diagnosis and genetic counseling.

Humans↗
PubMed1991

Genetic events in breast cancer and their clinical correlates.

The great heterogeneity of clinical breast cancer probably reflects heterogeneity of the mechanisms that are involved in its genesis and in disease progression. Genetic events that may be critical for tumor etiology, may determine tumor characteristics, and may contribute to tumor evolution should differ among individuals and among individual tumors and may distinguish subgroups with varying prognoses. We approach this problem from two viewpoints: one is based on population studies and the other on genetic events at the cellular level. 1. Population-based questions: What susceptibility factors are associated with individuals and groups who develop tumors? Inheritance patterns, familial aggregates, and associations with other tumors and other genetic diseases have been described for breast cancer. Bilateral and multifocal tumors may be examples of inherited predisposition, and their clinical and biological characteristics should be informative. Are there associations with tumor identifiers, such as histologic type and other tumor markers, for any of the "increased susceptibility" states? 2. Tumor-derived information: What types and frequencies of genetic alterations are found; do they relate to stage of tumor evolution, to morphologic classification, or to clinical evidence of comparative malignancy? Genetic evaluation depends upon cytogenetic and cytometric methods at the cellular level, and on detection of mutation, gene deletion, or amplification at the molecular level. We examine whether observed genetic alterations suggest mechanistic bases for morphologic distinctions among breast cancers and whether they assist in defining clinical phenotypes or steps in tumor progression. The general conclusions are that breast cancer comprises a complex set of neoplasms, that there is as yet little evidence to favor a final common pathway for its origin, and that a wide range of biological perturbations underlie its clinical course in the individual patient. An understanding of the basic mechanisms, their variety, and which of them apply in individual cases, is necessary as a rational basis for classification and for the development of strategies to interfere with tumor development in high-risk individuals.

Breast Neoplasms↗
PubMed1989

Diamond-blackfan anemia: etiology, pathophysiology, and treatment.

Diamond-Blackfan anemia (DBA) is manifested by a wide variety of clinical and in vitro abnormalities. Despite this biological diversity, the hematological phenotype is remarkably similar for all patients and consists of a normochromic-macrocytic anemia in early childhood, reticulocytopenia, and a normocellular marrow with a selective deficiency of red cell precursors. Fetal hemoglobin is usually increased, distributed heterogeneously, has a fetal G gamma/A gamma pattern, and is associated with increased expression of red cell i antigen. Although most cases are sporadic, there are examples of autosomal recessive and autosomal dominant inheritance patterns. Approximately 70% of patients with DBA respond to prednisone, and many can be maintained on tapered doses. Those who are steroid-dependent at high dosage as well as those who do not respond are managed on a transfusion and iron chelation program. Claims of efficacy for other therapies, such as cyclosporine or high-dose intravenous methylprednisolone, require substantiation. Bone marrow transplantation has been successfully performed in patients who have tissue-matched donors, and the procedure cures the anemia. Recombinant growth factors may be a therapy of the future. Regarding pathophysiology, initial reports of humoral or cellular inhibitors of erythropoiesis were not confirmed in all laboratories. However, some patients have lymphocyte dysfunction with decreased T cells, decreased T4/T8 ratios, and defective lymphocyte-mediated suppression of lymphoproliferation. A large body of data indicates that the erythroid stem cells are intrinsically defective in DBA, and they are partly or completely refractory to erythropoietin. The role of elevated red cell adenosine deaminase activity in the pathogenesis of this abnormal erythropoiesis is not clear, but this finding is characteristic of the syndrome in most patients. Present studies using recombinant growth factors have demonstrated a diversity of defects in erythropoiesis in patients with DBA. Blocks in red cell production and red cell maturation were seen at various levels along the differentiation pathway. Of clinical interest, interleukin-3 has a corrective effect in vitro on the aberrant marrow erythropoiesis of steroid-refractory patients, and, hence, it may have therapeutic application.

Adrenal Cortex Hormones↗
PubMed1984

Chromosome polymorphism involving heterochromatic blocks in Chinese hamster chromosome 9.

A chromosome polymorphism was detected between two early passage euploid Chinese hamster cell strains when a fluorescence shift of the small metacentric No. 9 chromosome was resolved by flow cytometry. The characteristics of the polymorphism were studied using cultures established from ear clippings taken from 16 additional hamsters from our breeding colony. Additional variants of chromosome 9 were detected using flow cytometry, and a subset of these variants were analyzed by G- and C-banding. An increase of fluorescence recorded by flow cytometry correlated with an increase of centromeric heterochromatin. Autosomal normalization of the flow karyotype from 18 different animals indicated three distinct peak positions for chromosome 9. The results indicate that a discrete block of constitutive heterochromatin may be present in one or two extra copies within the small inbred colony of hamsters studied. To determine the inheritance patterns, hamsters with known polymorphic No. 9 chromosomes were bred. The flow karyotypes derived from the offspring of these matings provide strong evidence that chromosomal polymorphisms are inherited in Mendelian fashion.

Animals↗
PubMed1975

Polymporphism of human C-band heterochromatin. II. Family studies with suggestive evidence for somatic crossing over.

An analysis of the inherited pattern of C-band heterochromatin has been made in five pedigrees containing a total of 33 offspring that were available for analysis. The majority of variants were found to be inherited; however, at least seven of the 99 variants were not present in either parent, and an additional seven differed from the parental variant by either a morphological change or the appearance of mosaicism. It is believed that the polymorphism of human constitutive heterochromatin arises from a mismatching of the repetitive DNA sequences contained in these regions with subsequent unequal crossing over. Further, the observed mosaic patterns provide suggestive evidence that such an event occurs in somatic cells as well as during meiosis.

Blood Group Antigens↗
PubMed1996

The genetic basis of hereditary blistering disorders.

Inherited blistering disorders have been classified by inheritance pattern, ultrastructural morphology and level of skin cleavage, and immunofluorescence detection of cutaneous antigens. During the past 5 years, investigators have discovered the molecular bases for the major inherited blistering disorders, epidermolytic hyperkeratosis, epidermolysis bullosa simplex, epidermolytic palmoplantar keratoderma, junctional epidermolysis bullosa, and dystrophic forms of epidermolysis bullosa. In addition to providing answers to patients about the underlying mechanisms of these devastating blistering disorders, the discoveries have provided insight into the function of several cutaneous proteins and have led to the ability to diagnose prenatally these lifelong conditions through genetic analysis in affected families.

Child, Preschool↗
PubMed1975

Allozyme genetics in permanent translocation heterozygotes of the Oenothera biennis complex.

Allozyme inheritance and transmission genetics of 11 enzyme systems were determined in the permanent translocation heterozygotes Oenothera biennis, Oe. strigosa, and Oe. parviflora. Electrophoretic variation was examined first among 164 strains of structural heterozygotes. Allelic configurations were then judged from inheritance patterns in reciprocal F1 hybrids between each of 22 ring-forming strains and tester strains of the related bivalent-formers, Oe. hookeri and Oe. grandiflora. Allozymes are inherited as codominant markers, and, as dictated by the genetic system, within a strain individual allelic variants are generally transmitted through only one germ line. Of the 20 loci resolved, only eight are polymorphic in any species, and, within species, generally only two alleles are present at each polymorphic locus. Despite the relatively meager allelic array, each of the 22 strains whose chromosome complexes were characterized is genotypically unique. Generally, within taxa, alpha (egg) and beta (sperm) complexes differ in allele frequency at several polymorphic loci. Such variability is correlated with differences in the phylogenetic origins of complexes and not with differences in segmental arrangement within a group of related complexes.

Alleles↗
PubMed1992

Evidence for paternal imprinting in familial Beckwith-Wiedemann syndrome.

A previously unreported family in which seven members in two generations have Beckwith-Wiedemann syndrome (BWS) is documented. Paternal imprinting of the gene responsible for BWS is involved as the mechanism responsible for the aberrant inheritance pattern in this kindred. A review of published reports showed 27 previously published pedigrees with two or more affected subjects with BWS. Paternal imprinting would explain the non-mendelian inheritance of BWS in all but four kindreds. The latter families are examined in more detail and in only one example is the evidence against imprinting totally unexplained.

Beckwith-Wiedemann Syndrome↗
PubMed1986

Intellectual and cognitive function in adults with myotonic muscular dystrophy.

Intellectual and cognitive function was studied in 43 patients (21 men and 22 women) with myotonic muscular dystrophy (MMD). The inheritance distribution was 18 paternal, 10 maternal, and 15 unknown. All patients received the Wechsler Adult Intelligence Scale-Revised, the Wechsler Memory Scale, the Halstead-Reitan Neuropsychological Test Battery, and the Aphasia Screening Test. Significantly lower scores (p less than 0.05) were found on all intellectual and cognitive impairment tests in both men and women of the maternal inheritance MMD subgroup, compared with the paternal inheritance MMD subgroup and with the normative data. Scores for patients with paternally inherited disease did not differ significantly from normative data for verbal, performance, or full scale intelligence quotients and memory quotients. There were no significant differences in intellectual and cognitive test scores between men and women for the group as a whole, for the maternal inheritance subgroup, or for the paternal inheritance subgroup. It is suggested that inheritance pattern is a necessary variable in studies investigating intellectual and cognitive function in MMD. Although the reason for the association of lower intellectual and cognitive function in MMD of maternal inheritance is not known, the data presented here may be useful for genetic counseling.

Adolescent↗
PubMed1995

Developmental regulation of genomic imprinting during gametogenesis.

Successful mammalian development requires both the male and female genomes. This is due in part to genomic imprinting, which results in offspring inheriting only one functional copy of a gene from either the mother or the father. Evidence suggests that this specialization of the parental genomes is established during gametogenesis when the imprint pattern inherited from the parent is switched to reflect the sex of the progeny. We used reverse transcription-PCR to analyze the allele-specific expression of Igf-2, Igf-2r, and H19 in the testes and ovaries of mice derived from an interspecies cross between Mus musculus and Mus spretus. Because of genomic imprinting, Igf-2 is expressed only from the paternal allele and Igf-2r and H19 only from the maternal allele, in most tissues. Although allele-specific expression was maintained in the neonatal testis and ovary, relaxation of imprinting was detected by 7 days after birth in the male and continued during testis development. In the female, relaxation of the Igf-2 and Igf-2r parental imprints was observed in the adult ovary and oocyte. These results (1) indicate that imprinted expression is relaxed during gametogenesis, presumably as a consequence or prerequisite of the imprinting mechanism, and (2) predict a subsequent imprinting event after which the allele-specific expression of Igf-2, Igf-2r, and H19 reflects the parent of origin.

Alleles↗
PubMed1976

Craniosynostosis, midfacial hypoplasia and foot abnormalities: an autosomal dominant phenotype in a large Amish kindred.

An unusual spectrum of craniofacial and foot abnormalities has been detected within a large midwestern Amish kindred. Enlarged great toes and craniofacial abnormalities suggested Pfeiffer acrocephalosynadactyly type V; however, thumb abnormalities were not present. Eighty-eight affected individuals were observed and another 50 were reliably reported to be affected. An autosomal dominant inheritance pattern was observed associated with variable expressivity. All affected individuals had some clinical or radiologic abnormality of the feet. The phenotypic expression was so variable that the entire spectrum of dominantly inherited craniofacial dysotoses-acrocephalosyndactylys (except the typical Apert syndrome) was seen within this kindred.

Child, Preschool↗
PubMed1997

Identification of a complex congenital heart defect susceptibility locus by using DNA pooling and shared segment analysis.

The identification of genetic loci involved in most forms of congenital heart disease has been hampered by the complex inheritance patterns of these disorders. Atrioventricular canal defects (AVCDs) are most commonly associated with Down syndrome, although non-syndromic cases also occur. Non-syndromic AVCDs have been attributed to multifactorial inheritance. However, the occurrence of a few kindreds with multiple affected individuals has suggested that a major genetic locus can account for the disorder in some families. We have used a combination of DNA pooling and shared segment analysis to perform a high density screen of the entire autosomal human genome in an extended kindred. In so doing, we have identified a genetic locus on chromosome 1 shared by all affected individuals. Our data demonstrate the existence of a congenital heart defect susceptibility gene, inherited as an autosomal dominant with incomplete penetrance, involved in AVCD. Furthermore, our data demonstrate the power of using key isolated kindreds in combination with high density genomic screens to identify loci involved in complex disorders such as congenital heart defects.

Chromosome Mapping↗
PubMed1995

Periodic catatonia: a schizophrenic subtype with major gene effect and anticipation.

In a family study involving 139 probands with DSM-III-R catatonic schizophrenia and 543 first-degree relatives, we investigated age-specific morbidity risk according to Leonhard's clinical distinction between systematic and periodic catatonia. This dichotomy is based on different types of symptomatology, course, and outcome. In systematic catatonia the age-corrected morbidity risk was 4.6%. In periodic catatonia, however, there was an age-corrected morbidity risk with homogenous psychoses of 26.9%, and more parents than siblings were affected. This points strongly to a major gene effect in periodic catatonia. Furthermore, a pairwise comparison of patients and their parents revealed patterns of anticipation, i.e., the probands' age at the onset of disease was significantly earlier than that of their parents (P < 0.001). Similarly, anticipation was apparent in pedigrees with three successive generations affected. This inheritance pattern with homogenous psychoses and anticipation indicates that genes with trinucleotid repeat expansion or other repetitive elements affecting gene expression may be involved in the etiology of periodic catatonia. Thus, periodic catatonia as a specific clinical subtype of schizophrenia is a promising candidate for molecular genetic evaluation.

Adult↗
PubMed1998

[Positional cloning of susceptibility genes for non-insulin-dependent diabetes mellitus].

Although studies of families and twin studies have demonstrated that non-insulin-dependent diabetes mellitus (NIDDM) has a strong genetic component, the genes responsible for the common forms of NIDDM are largely unknown, due to the complex and heterogeneous nature of the disease. To study the genetics of NIDDM, we used an inbred animal model of NIDDM, the NSY mouse, in which NIDDM spontaneously develops in an age-dependent manner. The inheritance pattern of glucose tolerance, fasting insulin levels, insulin response to glucose, body mass index, and epididymal fat pad weight in F 1 hybrids of NSY with control C3H/He mice suggested the different modes of inheritance in these phenotypes. Multipoint linkage analysis of glucose tolerance in F2 mice with microsatellite markers throughout the genome mapped at least three loci on different chromosomes. Positional cloning of susceptibility genes for NIDDM in NSY mice may increase our understanding of the genetics and etiology of human NIDDM and may lead to more effective methods for prevention and intervention.

Animals↗
PubMed1976

Deafness and vitiligo.

Seven cases of congenital deafness and an autosomal recessive pedigree pattern were observed in an inbred kindred. Three of the cases also had vitiligo, and there were 2 other cases of vitiligo in this kindred. The vitiligo also appeared to have an autosomal recessive inheritance pattern.

Deafness↗
PubMed1997

Further epidemiological evidence for anticipation in schizophrenia.

Anticipation describes an inheritance pattern within a pedigree in which disease severity increases, and/or age at onset decreases, in successive generations. This phenomenon has been described in different samples of schizophrenic subjects, and could explain many inconsistencies in the inheritability of schizophrenia. Anticipation is, however, subject to numerous and significant biases, partially controlled by different methodologies used in different studies. We analyzed the anticipation effect on an original sample of schizophrenic patients (n = 57) who had at least one other schizophrenic in their family belonging to another generation (father/mother, uncle/aunt, son/daughter). We tested the anticipation effect according to previously published methodologies, such as percentages of parent-child pairs showing negative versus positive anticipation, comparison of anticipation limited to parent-child or uncle-nephew pairs, anticipation analysis on the basis of families with unilineal origins only, and comparison of the age at onset-survival distribution of the two generations. The 31 schizophrenic subjects who belonged to the younger generation had a significantly earlier age at onset (24.58 years) than the 26 schizophrenic subjects who belonged to the older generation (36.46 years). Whatever the method used to control biases, we significantly found earlier age at onset for schizophrenic patients from the younger generation. There is strong evidence for the existence of the anticipation effect in schizophrenia in our sample, as well as in various others, which may elucidate numerous inconsistencies in clinical and epidemiological data which characterize schizophrenia. Looking for expanded trinucleotide repeats is thus the next step to detect the gene(s) that are potentially involved.

Adult↗
PubMed1997

Paternal transmission of the mouse Thp mutation is lethal in some genetic backgrounds.

Thp is a large deletion on chromosome 17 which includes the maternal lethal gene Tme. Documentation of inheritance patterns suggests that Tme is an imprinted gene which is required for viability; maternal deletion is lethal while paternal deletion is viable. However, paternal transmission of Thp is rarely the expected 50%. We show here that paternally inherited Thp is lethal in some strains, providing evidence of an incompletely penetrant, dosage sensitive lethal allele of a locus that probably maps to the hairpin tail region of chr. 17. Interpretation of the various phenotypes associated with loss of the putative Tme gene, Igf2r, may need to be revised in view of these observations.

Abnormalities, Multiple↗