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PubMed2006

Regional brain metabolite abnormalities in inherited prion disease and asymptomatic gene carriers demonstrated in vivo by quantitative proton magnetic resonance spectroscopy.

INTRODUCTION: Inherited prion diseases are caused by mutations in the gene which codes for prion protein (PrP), leading to proliferation of abnormal PrP isomers in the brain and neurodegeneration; they include Gerstmann-Sträussler-Scheinker disease (GSS), fatal familial insomnia (FFI) and familial Creutzfeldt-Jakob disease (fCJD). METHODS: We studied two patients with symptomatic inherited prion disease (P102L) and two pre-symptomatic P102L gene carriers using quantitative magnetic resonance spectroscopy (MRS). Short echo time spectra were acquired from the thalamus, caudate region and frontal white matter, metabolite levels and ratios were measured and z-scores calculated for individual patients relative to age-matched normal controls. MRS data were compared with structural magnetic resonance imaging. RESULTS: One fCJD case had generalised atrophy and showed increased levels of myo-inositol (MI) in the thalamus (z=3.7). The other had decreased levels of N-acetylaspartate (z=4) and diffuse signal abnormality in the frontal white matter. Both asymptomatic gene carriers had normal imaging, but increased frontal white matter MI (z=4.3, 4.1), and one also had increased MI in the caudate (z=5.3). CONCLUSION: Isolated MI abnormalities in asymptomatic gene carriers are a novel finding and may reflect early glial proliferation, prior to significant neuronal damage. MRS provides potential non-invasive surrogate markers of early disease and progression in inherited prion disease.

Adult↗

PubMed2002

Major histocompatibility complex controls susceptibility and dominant inheritance, but not the severity of the disease in mouse models of rheumatoid arthritis.

Collagen-induced arthritis (CIA) in DBA/1 and proteoglycan-induced arthritis (PGIA) in BALB/c mice are the most frequently used mouse models for studying clinical, immunological and genetic factors contributing to rheumatoid arthritis. DBA/1 ( H2(q)) mice are susceptible to CIA but resistant to PGIA, whereas BALB/c mice ( H2 (d)) are susceptible to PGIA and resistant to CIA. To gain insight into the mechanisms of how the major clinical (disease susceptibility, severity and onset of arthritis) and immunological traits (antigen-specific T- and B-cell responses) are influenced by the major histocompatibility complex (MHC), we have generated a unique intercross of BALB/c and DBA/1 parent strains, and the F1 and F2 hybrids were immunized for either CIA or PGIA. The major clinical and immunological traits were identified as either binary (qualitative) or quantitative traits on Chromosome 17 with a peak at MHC when the entire population was analyzed. In contrast, when only arthritic (susceptible) mice were selected and analyzed, the major clinical traits (severity and onset) 'lost' the linkage to MHC. Thus, MHC dictates disease susceptibility, but not the severity of arthritis. This was even more evident in the case of the H2(q) allele, which was clearly responsible for the dominant inheritance of arthritis in F2 hybrids (either CIA or PGIA). In conclusion, while certain MHC alleles strongly affect disease susceptibility and determine the mode of inheritance of a polygenic autoimmune disease, neither the type of inheritance (dominant vs recessive) nor other MHC components have evident effects upon the clinical symptoms of arthritis.

Animals↗

PubMed2001

Genome-wide linkage analysis of inherited hydrocephalus in the H-Tx rat.

Inherited hydrocephalus in humans has received very little attention, most probably because known occurrences are sporadic and systematic investigation is difficult. The H-Tx rat, one of a number of rodent strains with inherited hydrocephalus, has a complex inheritance with more than one postulated susceptibility gene and 40% penetrance. The aim of this study was to perform a genome-wide scan on backcross progeny derived from H-Tx and Fisher F344 rats, to identify genomic regions associated with hydrocephalus. Penetrance of hydrocephalus in (H-Tx x F344) F1 x H-Tx was 12.3%. All severely hydrocephalic progeny (n = 185) and a subset of normal progeny (n = 128) were screened with 110 simple sequence length polymorphisms (SSLPs) with 83% coverage of the genome. A significant susceptibility locus was found on chromosome (Chr) 11 (LOD = 3.1). Three loci with suggestive linkage were found on Chr 17 (LOD = 2.4), on Chr 9 (LOD = 1.94), and on Chr 19 (LOD = 1.91). For the loci on Chr 11 and 19, hydrocephalus was associated with the heterozygous genotype, while the other two were recessive. Although none of the four loci was essential for the hydrocephalic phenotype, the additive effects of two, three, or four loci increased the penetrance in a linear fashion. Altogether these four loci accounted for 13.5% of the total variance. It is concluded that hydrocephalus in the H-Tx rat is associated with two, possibly four genetic loci, but that there may be additional undefined genetic and environmental influences.

Animals↗

PubMed2001

Dominantly inherited myopathy with novel tubular aggregates containing 1-21 tubulofilamentous structures.

Tubular aggregates (TAs) in skeletal muscle fibers have been observed as a nonspecific finding in a number of different conditions such as periodic paralysis, myotonic disorders, hyperaldosteronism, chronic use of drugs, and alcoholism. However, TAs were also found more specifically in well-defined muscle disorders, e.g., exercise-induced cramps, myasthenic syndromes, and even in dominantly or recessively inherited familial myopathies. We report on a presumably dominantly inherited familial myopathy with late onset characterized morphologically by the presence of three types of TAs in type II muscle fibers identified in three affected members of one family (a 86-year-old man and his two sons). The first, novel type was characterized by tubules, 30-200 nm in thickness which included 1-21 tubulofilamentous structures 14-18 nm in diameter. The second type of TAs corresponded to previously well-described tubules and were derived from terminal cisternae, which were rather irregularly arranged or widened, and filled with material of medium electron density. The third type of TAs were occasional, hexagonally arranged TAs of the usual type [type Ib and Ic]. Rare annulate lamellae were also seen. Our findings support the evidence of tubular aggregates as the major finding in certain dominantly inherited myopathies. Tubules of the first type, to the best of our knowledge, have not been recorded in any other myopathy. It is therefore suggested that these tubules characterize a novel type of a benign, slowly progressive myopathy with late onset, muscle pain, cramps, and stiffness.

Adult↗

PubMed2005

DNA methylation and epigenetic inheritance during plant gametogenesis.

In plants, newly acquired epigenetic states of transcriptional gene activity are readily transmitted to the progeny. This is in contrast to mammals, where only rare cases of transgenerational inheritance of new epigenetic traits have been reported (FASEB J 12:949-957, 1998; Nat Genet 23:314-318, 1999; Proc Natl Acad Sci U S A 100:2538-2543, 2003). Epigenetic inheritance in plants seems to rely on cytosine methylation maintained through meiosis and postmeiotic mitoses, giving rise to gametophytes. In particular, maintenance of CpG methylation ((m)CpG) appears to play a central role, guiding the distribution of other epigenetic signals such as histone H3 methylation and non-CpG DNA methylation. The evolutionarily conserved DNA methyltransferase MET1 is responsible for copying (m)CpG patterns through DNA replication in the gametophytic phase. The importance of gametophytic MET1 activity is illustrated by the phenotypes of met1 mutants that are severely compromised in the accuracy of epigenetic inheritance during gametogenesis. This includes elimination of imprinting at paternally silent loci such as FWA or MEDEA (MEA). The importance of DNA methylation in gametophytic imprinting has been reinforced by the discovery of DEMETER (DME), encoding putative DNA glycosylase involved in the removal of (m)C. DME opposes transcriptional silencing associated with imprinting activities of the MEA/FIE polycomb group complex.

CpG Islands↗

PubMed2007

Evaluation of advanced glycation end-products in diabetic and inherited canine cataracts.

BACKGROUND: The receptor for advanced glycation end-products (RAGE) increases in the human cataract and should correlate with increased DNA damage and proliferation of lens epithelial cells (LECs). The purpose of this study was to measure and immunolocalize RAGE in normal and cataractous canine LECs, and to determine whether there was a correlation between RAGE and DNA damage (gadd45), cell-cycle regulation (p21), and LEC proliferation (proliferating cell nuclear antigen, PCNA). METHODS: Thirty-two anterior lens capsules from 22 dogs that underwent cataract surgery and 10 lenses from dogs with normal eyes were evaluated. Eleven of the cataractous lenses were from diabetic patients (n=16), and eleven were from patients with inherited cataracts (n=16). Standard immunohistochemical staining was performed using antibodies against RAGE, gadd45, p21, PCNA, alpha-smooth muscle actin, and TGF-beta. Immunostaining intensity for each antibody was given a score of 0-4+. Standard Western blot analysis on normal and cataractous lens capsules was performed using the same antibodies as in the immunohistochemical staining. Comparisons were also made based on age and sex. Real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) was performed for RAGE. RESULTS: There was an increase in RAGE expression with age in normal LECs, but no significant difference was seen when normal adult LECs were compared to cataractous LECs. The stage of the cataract and the presence of LIU were not associated with a significant increase in RAGE expression. There was no age-dependent difference in the normal lenses for gadd45, p21, or PCNA. Significant up-regulation of p21 (P < 0.05) and PCNA (P < 0.05) was seen in diabetic cataracts compared to inherited cataracts. CONCLUSION: RAGE and PCNA expression did not increase with cataractogenesis, possibly due to overexpression associated with normal aging and constant exposure to oxidative stress from sunlight-related ultraviolet irradiation, respectively. However, p21 and PCNA increased in diabetic cataractogenesis suggesting cell cycle and proliferation dysregulation. This may be related to the rapid onset in this type of cataract compared with the more chronic and slower-to-develop inherited cataracts.

Animals↗

PubMed1999

Histopathological changes in iridocorneal angle of inherited glaucoma in rabbits.

BACKGROUND: We examined morphologically the angular region of eyes affected by inherited glaucoma in rabbits genetically developed by crossbreeding in order to investigate the etiologic changes in the iridocorneal angle and to establish whether this strain of rabbit is a suitable animal model of goniodysgenetic glaucoma in humans. METHODS: The angular regions of both normal and glaucomatous eyes from four rabbits having unilateral inherited glaucoma were observed with light and electron microscopy. RESULTS: In the glaucomatous eyes angular region, the aqueous plexus corresponding to Schlemm's canal in humans was open and located far peripherally to the peripheral margin of the anterior chamber angle, although the plexus of one glaucomatous eye was poorly developed with a small lumen. In the angular meshwork, which corresponds to the trabecular meshwork in humans, a thick abnormal tissue with round cells embedded in the extracellular matrix was located just beneath the plexus. A large amount of extracellular matrix of basal lamina-like material was observed in the thick tissue. In the normal eyes, the angular region consisted of well-developed trabecular sheets with neither a thick tissue nor accumulations of extracellular matrix in the angular meshwork. CONCLUSION: The findings observed in the glaucomatous eyes are much the same as those observed in goniodysgenetic glaucoma in humans, suggesting that this strain of inherited glaucoma rabbits is a suitable animal model of goniodysgenetic glaucoma in humans. The present study also supports the hypothesis that the presence of a thick subcanalicular tissue due to maldevelopment of the iridocorneal angle is one of the main causes of this type of glaucoma.

Animals↗

PubMed1997

Kinetoplast DNA minicircles are inherited from both parents in genetic crosses of Trypanosoma brucei.

In the order Kinetoplastida, genetic exchange has been demonstrated only in the genus Trypanosoma. Analysis of kinetoplast DNA (kDNA) in genetic crosses of T. brucei has shown that whereas maxicircles are inherited uniparentally, minicircles are inherited from both parents. This result was confirmed for a new cross of T. b. brucei and T. b. rhodesiense by restriction enzyme digestion and Southern analysis of purified kDNA. By hybridisation with small minicircle-derived probes, we could demonstrate the presence of particular parental minicircles in the kDNA of hybrid progeny clones. All hybrid clones had inherited two minicircles from one parent despite two of the four clones having maxicircles from the other parent. The results suggest that rather than small-scale exchange of minicircles between parental networks, gross breakdown and reassembly of the minicircle network occurs during genetic exchange.

Animals↗

PubMed2005

Julia Bell and the Treasury of Human Inheritance.

The Treasury of Human Inheritance represents the most extensive, and one of the earliest series of documentations and analyses of human genetic disorders. Published between 1909 and 1958, from The Galton Laboratory, London, most of the numerous sections were written by Julia Bell, who represents a key figure in the development of human and medical genetics. Her combination of mathematical training, genetic knowledge and clinical expertise yielded numerous important insights into human inheritance first appearing in the Treasury; it remains a valuable scientific as well as an historical record of the genetics of a range of important inherited disorders.

Genetics, Medical↗

PubMed2004

Inherited colorectal cancer registries in the United States.

PURPOSE: The prevalence of familial adenomatous polyposis-associated cancers in the United States has been conservatively estimated at 15,000, and that of hereditary nonpolyposis colorectal cancer (HNPCC)-associated cancers at 30,000. Every blood descendant of each of these patients is at risk of carrying a germline mutation predisposing them to early onset colorectal and other cancers. Optimal care of these high-risk families involves a center with expertise in the syndromes. This study was performed to see how many such centers exist in the United States and to learn something of how they work. METHODS: The mailing lists of three international societies concerned with inherited colorectal cancer were used to send surveys inquiring about the presence of a registry or center, and how that center worked. The Collaborative Group of the Americas, the Leeds Castle Polyposis Group, and the International Collaborative Group on hereditary nonpolyposis colorectal cancer were queried. RESULTS: There were 30 centers in the United States: 26 responded, representing 15 states. Eighteen centers that responded had registries for inherited colorectal cancer. There were 1,396 familial adenomatous polyposis families among the 18 registries, 2,058 hereditary nonpolyposis colorectal cancer families, 42 with juvenile polyposis, and 216 with Peutz-Jehger's syndrome. The 18 registries employed 29 genetic counselors or coordinators. Seven used Microsoft Access as a database, five used Progeny, three a SQL server-based system, one Filemaker Pro, one Microsoft Excel and one used Oracle. Cyrillic was the pedigree-drawing program in 6 registries, Progeny in 12, and Ped Draw in 1. Hereditary nonpolyposis colorectal cancer was defined using the Amsterdam I criteria by four registries, Amsterdam II by five, both criteria by six, Bethesda guidelines by one, and by genotype alone in two registries. CONCLUSIONS: The United States is underserved by registries for inherited colorectal cancer, having enrolled only a small proportion of the families theoretically available. Registries differ in fundamental aspects of function. More collaboration and more registries are needed.

Colorectal Neoplasms↗

PubMedDate not supplied

Differential organellar inheritance in Passiflora's (Passifloraceae) subgenera.

Four chloroplast (cp), one mitochondrial (mt), and one ribosomal nuclear (ITS) DNA regions were studied in four artificial and one natural interspecific Passiflora hybrids. The ITS results confirmed their hybrid origin and all mtDNAs were maternally inherited. The same, however, was not true for cpDNA. The four hybrids (three artificial and one natural) derived from species of the Passiflora subgenus showed a cpDNA paternal inheritance, while the one involving taxa of the Decaloba subgenus gave evidence of maternal transmission. These results are of significance for the ongoing studies which are being performed on the molecular evolution of this genus and furnish important background for investigations aimed at clarifying the factors which determine cpDNA inheritance.

Base Sequence↗

PubMed1987

Inherited deficiency of properdin and C2 in a patient with recurrent bacteremia.

A nine-year-old white boy with recurrent pneumococcal bacteremia is described. His serum had no hemolytic activity in either the classic or alternative complement pathways. Absence of classic pathway activity was secondary to a homozygous deficiency of C2. The parents had half-normal levels of C2, compatible with an autosomal recessive mode of inheritance. Measurement of serum properdin levels by radial immunodiffusion and enzyme-linked immunoabsorbent assay revealed a profound deficiency in the patient, normal levels in the father, and half-normal levels in the mother, suggesting X-linked inheritance of the deficiency. Addition of purified properdin to the patient's serum fully reconstituted the alternative pathway function. This patient's unique combination of inherited deficiencies of properdin and C2 is a likely explanation for his susceptibility to bacterial infection.

Child↗

PubMed1995

Are mitochondria inherited paternally in Ascaris?

Mitochondrial DNA (mtDNA) is finding increasing usage as a tool for studying the systematics, population genetics and epidemiology of parasitic helminths, and is generally assumed to be inherited maternally. Yet two features of Ascaris biology--fertilization by large amoeboid sperm and some novel aspects of sperm mitochondria--suggest a paternal component to mitochondrial inheritance in this organism. In this study, we compare mtDNA restriction patterns of parental worms with those of their progeny but find no evidence for paternal inheritance. We suggest that sperm-derived mitochondria are actively destroyed or outcompeted by maternal organelles in the zygote.

Animals↗

PubMed1992

Inheritability of atherosclerosis and the role of lipoproteins as risk factors in the development of atherosclerosis in WHHL rabbits: risk factors related to coronary atherosclerosis are different from those related to aortic atherosclerosis.

Inheritability of atherosclerosis and the influences of serum lipids on atherosclerosis were examined by following its progression in selectively bred WHHL rabbits. Our studies indicate (1) coronary atherosclerosis is clearly inherited from parents by offspring whereas inheritability of aortic atherosclerosis is uncertain; (2) coronary stenosis is positively correlated to serum cholesterol level, although the correlation coefficient is markedly low: in contrast, no relationship between serum lipid levels and aortic atherosclerosis was observed; (3) cholesterol-rich VLDL showed atherogenicity in aorta, but not in coronary arteries; (4) an unknown lipoprotein detected by 3.6% polyacrylamide gel electrophoresis was related to coronary atherosclerosis, although no relationship between the unknown lipoprotein and aortic atherosclerosis was observed. These findings suggest that there are two types of genetic factors involved in atherosclerosis, one of which is unique to coronary atherosclerosis whereas the other is related to only aortic atherosclerosis.

Animals↗

PubMed1992

Inheritance of the replication complex by one of two daughter copies during lambda plasmid replication in Escherichia coli.

Direct measurement of DNA synthesis confirmed that lambda plasmid replication proceeds for several hours in an amino acid-starved relA mutant of Escherichia coli, leading to plasmid amplification; this replication is lambda cro-independent, but requires the function of lambda O initiator in the absence of its synthesis. This suggests that after the assembly of the replication complex (RC) at ori lambda the lambda O protein remains in this structure and the affinity of lambda O to ori lambda is alleviated in the assembled RC allowing its movement along the DNA. During amino acid starvation the lambda plasmid DNA synthesis per bacterial mass occurs at a constant level, as would be expected if the number of functioning RCs remained constant. This favors the idea that under these conditions the next replication round operates due to the activity of the RC inherited from the preceding round. Density shift experiments reveal indeed that, from two daughter plasmid copies synthesized after the onset of amino acid starvation only one is able to enter into the next round of replication. We infer that this is the plasmid copy that inherits the lambda O-enclosing RC from the previous replication round. Moreover, the same results of density shift experiments were obtained for plasmids synthesized before the onset of amino acid starvation. Therefore, we presume that in lambda plasmid-harboring bacteria growing in nutrient medium, every second plasmid circle bears an RC that originates from the preceding round of replication. This structure has to be assembled de novo only on the daughter plasmid copy that does not inherit the parental RC. In the absence of lambda O initiator synthesis in amino acid-starved relA cells this process cannot occur, leaving as the only replication pathway that driven by the parental RC. Our results are discussed in relation to the model of regulation of lambda plasmid replication.

Bacteriophage lambda↗

PubMed1991

Glucose intolerance in first-degree relatives of patients with Friedreich's ataxia is associated with insulin resistance: evidence for a closely linked inherited trait.

Multiple and different genetic defects may be associated with the development of diabetes mellitus. Friedreich's ataxia (FA) is an autosomal recessively inherited neurologic disease associated with a high prevalence of diabetes. We previously demonstrated that patients with FA have insulin resistance prior to the development of overt diabetes mellitus. To determine if insulin resistance is an inherited characteristic in this group, we performed oral glucose tolerance tests (OGTT) on first-degree relatives, 21 parents and 17 siblings, of patients with FA. While fasting concentrations were normal, both glucose and insulin concentrations in response to oral glucose were significantly elevated compared with controls. Corrected insulin responses, CIR = I x 100/G (G-70) (I = insulin, G = glucose), were not different from controls, whereas peripheral insulin activities, A = 10(4)/Ip Gp (p = values of I and G at peak glucose concentration), were significantly decreased (FA, 0.66 +/- 0.11, P less than .001; parents, 0.63 +/- 0.06, P less than .001; siblings, 0.72 +/- 0.09, P less than .01; v controls, 1.52 +/- 0.19), indicating the presence of insulin resistance in patients and first-degree relatives. Multiple discriminant analysis was used to separate patients with FA from controls. The combination of GLUT (sum of glucose values 0 to 3 hours of the OGTT) and CIR achieved significant separation (P less than .0004). Subsequent assignment of the relatives showed that 17 of 18 parents and 11 of 16 siblings (69%) fell in the range of FA, rather than with controls. These data suggest that insulin resistance is an inherited trait in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗

PubMed1992

Combined inherited protein S and heparin co-factor II deficiency in a patient with upper limb thrombosis: a family study.

A 42-year-old Italian woman presenting with spontaneous deep vein thrombosis of the right arm, was found to have inherited a deficiency of both protein S (PS) and heparin co-factor II (HC II). The two defects seemed to segregate independently, since her son exhibited only a HC II deficiency while one of her sisters manifested only the PS defect. All affected patients appeared heterozygous for one or other or both deficiency states. The proposita and her sister exhibited a congenital PS deficiency consisting of normal or near normal levels of total PS antigen and C4b-binding protein (C4b-BP) but a moderate reduction both of free PS antigen and of PS functional activity. In addition, the proposita and her son had half normal levels of HC II antigen and activity. Except for the proposita, all were asymptomatic. Inherited deficiencies either of PS or of HC II have been associated with thrombotic manifestations. Since the proposita had an inherited combined defect of the two proteins, severe thrombotic events might be expected. However, this was not found to be the case. The role of HC II deficiency in the pathogenesis of thrombosis whether alone or combined remains to be fully investigated.

Adolescent↗

PubMed1993

A mating type-linked gene cluster expressed in Chlamydomonas zygotes participates in the uniparental inheritance of the chloroplast genome.

A characteristic feature of early zygote development in Chlamydomonas is the selective degradation of chloroplast DNA from the mating type minus parent. The zygote-specific gene cluster ezy-1 is linked to the mating type locus and is transcribed almost immediately upon zygote formation. We show here that the acidic Ezy-1 polypeptide is rapidly transported to both the plus and minus chloroplasts, where it interacts with each chloroplast nucleoid. Expression of ezy-1 is selectively inhibited when plus, but not minus, gametes are briefly ultraviolet irradiated just prior to mating, a treatment known to disrupt the uniparental inheritance of chloroplast traits. We propose that the Ezy-1 polypeptide participates in the destruction of the minus chloroplast DNA in zygotes and thus the uniparental inheritance of chloroplast traits. The ezy-1 gene represents a valuable molecular probe for dissecting mechanisms underlying organelle inheritance.

Amino Acid Sequence↗