Genomic imprinting and its role in Prader-Willi and Angelman syndromes

Published and our own data, included in the CHRODYS database, on the dependence of phenotypic abnormalities in mono-, di-, and trisomics at human chromosome 15 on its parental origin are reviewed. The concept is confirmed that Prader-Willi and Angelman syndromes result from the combined effect of gene or chromosome mutations impairing the expression of syndrome-specific genes and from genomic imprinting, i.e., repression of corresponding genes received from one of the parents.     

Diagnostic testing for Prader-Willi and Angelman syndromes: response

Between 1992 and 1997, every year, approximately 30,000 examinations of the liver and bile ducts were done. Addition of colour Doppler imaging improves safety of procedures and allowed to perform ultrasound guided biopsy in 73 patients. On the basis of our experience we state that colour Doppler sonography guided percutaneous fine needle biopsy of the liver is useful, sufficient and safety diagnostic method of abscesses, cysts and malignant tumours of the liver.     

DNA-based diagnosis of Angelman syndrome and Prader-Willi syndrome

An endoscopically assisted technique for internally dividing the palmar or plantar annular ligament was developed in six cadaver limb specimens and two anesthetized horses. Under arthroscopic view, a slotted cannula was inserted into the digital sheath through a stab wound proximal to the annular ligament and advanced through the fetlock canal superficial to the flexor tendons with the slot oriented toward the fibers of the annular ligament. Division of the annular ligament by 90-degree tipped open and guarded blades was observed and verified by direct arthroscopic view. At necropsy, complete division of the annular ligament without iatrogenic damage to the neurovascular structures was confirmed by dissection. Annular ligament division was performed in seven horses with complex tenosynovitis conditions. Tenoscopic examination and removal of tendon and digital sheath adhesions, masses, and bands was followed by endoscopically assisted annular ligament transection. At follow-up, five horses were sound athletes without recurrent digital sheath problems, one horse had residual lameness, and one horse was still convalescing.     

Impact of genomic imprinting on genomic instability and radiation-induced mutation

A cross-sectional survey conducted among evening students was used to determine the prevalence of Wuchereria bancrofti infection in Maceió, capital of the State of Alagoas, northeast Brazil. A single thick-blood smear was used, being collected between 10 p.m. and 12 a.m. From a total of 29,551 students enrolled at evening elementary schools in the 33 city sectors, 16,569 (56.4%) were random selected for inclusion in the study. From those, 10,857 (65.5%) were interviewed and examined and 73 (0.7%) were found to have microfilaraemia. Autochthonous W. bancrofti carriers live in 10 of the 33 city sectors, suggesting a focal distribution. Moreover, 84% of infections were diagnosed among 29% of all students examined, inhabiting three contiguous sectors at the city central area, presenting infection rates up to 5.3%. Students living in city sectors with prevalence of microfilariae carriers greater than 1% were found to have a higher risk for infection when compared to students from the rest of the town [Relative Odds (RO) 12.8, 95% CI 6.7-25.1]. Eleven positive individuals from non endemic areas were living in Maceió for more than 10 years; time of residence in the area was a major risk factor for infection among students not born in the region (p < 0.01). Regarding sex, male students presented a higher proportion of positive (RO 1.7, 95% CI 1.1-2.9).     

The role of genomic imprinting in implantation

OBJECTIVES: To outline the possible role of the imprinted genes in early human embryogenesis and implantation. DATA IDENTIFICATION: Literature review. STUDY SELECTION: Studies examining the issues of genomic imprinting, implantation, gestational trophoblastic diseases, placental gene expression, and trophoblast invasion. RESULTS: Certain genes have been shown to be expressed either in the embryo or in the uterine decidua before implantation. Some of these have been shown to be parentally imprinted, that is, expressed either from their paternal or maternal origin. The paternally expressed genes are linked to placental proliferation and invasiveness. CONCLUSIONS: Clinical and basic data from different disciplines indicate that genomic imprinting may be crucial to the process of implantation.     

Prader-Willi and other syndromes associated with obesity and mental retardation

Constitutional obesity and mental retardation cooccur in several multiple congenital anomaly syndromes, including Prader-Willi syndrome, Bardet-Biedl syndrome, Cohen syndrome, Albright hereditary osteodystrophy, and Borjeson-Forssman-Lehmann syndrome as well as some rarer disorders. Although hypothalamic-pituitary axis abnormalities are thought to be a possible causative mechanism in some of these disorders, current knowledge is insufficient to explain the pathophysiologic mechanism of obesity in most multiple congenital anomaly/mental retardation syndromes. The chromosomal location of many of these syndromes is known, and studies are ongoing to identify the causative genes. Further delineation of the functions of the underlying genes will likely be instructive regarding mechanisms of appetite, satiety, and obesity in the general population. This review details current knowledge of the clinical and molecular genetic findings of multiple congenital anomaly/mental retardation syndromes associated with intrinsic obesity in an effort to delineate causative mechanisms and genetic abnormalities contributing to obesity.     

Parental antagonism, relatedness asymmetries, and genomic imprinting

The theory of inclusive fitness can be modified to consider separate coefficients of relatedness for an individual's maternal and paternal alleles. A gene is said to have parentally antagonistic effects if it has an inclusive fitness benefit when maternally derived, but an inclusive fitness cost when paternally derived (or vice versa). Parental antagonism favours the evolution of alleles that are expressed only when maternally derived or only when paternally derived (genomic imprinting).     

Do we understand the evolution of genomic imprinting?

Voltage-gated calcium channels can be classified into high voltage activated (HVA) and low voltage activated (LVA or T-type) subtypes. The molecular diversity of HVA channels primarily results from different genes encoding their pore-forming alpha1 subunits. These channels share a common structure with an alpha1 subunit associated with at least two regulatory subunits (beta, alpha2-delta). Any of the six alpha1-related channels identified to date are regulated in their functional properties through an interaction with the ancillary beta-subunit. By contrast, the diversity and the molecular identity of LVA or T-type calcium channels have yet to be defined. Whether LVA channels are modulated by a beta-subunit, like HVA channels, is unknown. To address this issue, we have used an antisense strategy to inhibit beta-subunit expression in the NG 108-15 neuroblastoma cell line. Differentiated NG 108-15 cells express both LVA and HVA channels. We found that LVA currents were unaffected when cells were incubated with beta-antisense, while HVA currents were drastically decreased. Since LVA Ca channel currents in NG 108-15 cells are not regulated by beta-subunits, it is reasonable to postulate that the pore-forming subunit(s) of these channels lacks an interaction domain with a beta-subunit (AID). This molecular feature, which is common to various T-type channels, indicates further that LVA calcium channels belong to a channel family structurally distant from HVA channels.     

Genetic conflicts, multiple paternity and the evolution of genomic imprinting

We present nine diallelic models of genetic conflict in which one allele is imprintable and the other is not to examine how genomic imprinting may have evolved. Imprinting is presumed to be either maternal (i.e., the maternally derived gene is inactivated) or paternal. Females are assumed to be either completely monogamous or always bigamous, so that we may see any effect of multiple paternity. In contrast to previous verbal and quantitative genetic models, we find that genetic conflicts need not lead to paternal imprinting of growth inhibitors and maternal imprinting of growth enhancers. Indeed, in some of our models--those with strict monogamy--the dynamics of maternal and paternal imprinting are identical. Multiple paternity is not necessary for the evolution of imprinting, and in our models of maternal imprinting, multiple paternity has no effect at all. Nevertheless, multiple paternity favors the evolution of paternal imprinting of growth inhibitors and hinders that of growth enhancers. Hence, any degree of multiple paternity means that growth inhibitors are more likely to be paternally imprinted, and growth enhancers maternally so. In all of our models, stable polymorphism of imprinting status is possible and mean fitness can decrease over time. Neither of these behaviors have been predicted by previous models.     

Mutation-selection balance under genomic imprinting at an autosomal locus

I model the effect of genomic imprinting on the equilibrium allele frequencies at an autosomal diallelic locus subject to viability selection and mutation. The population size is assumed to be very large; male and female mutation rates may be unequal. Different models examine cases of the inactivation of one gene (with both complete and partial penetrance) and of differential expression of genes according to the parent of origin. In the simplest cases the frequency of the deleterious allele is approximately twice that of a dominant nonimprinting mutant, but considerably less than that of a recessive nonimprinting mutant. Under imprinting, selection and unequal mutation rates interact: other things being equal, male-biased mutation leads to lower mutant frequencies under maternal imprinting and higher frequencies under paternal imprinting. I also model cases where just one allele is imprintable (and the other not). These models allow us to predict the frequency of a failure to imprint in a normally imprinting system, as well as the frequency of imprinting at a standard nonimprinting locus.     

Prader-Willi syndrome.

Although known for its distinctive food-related behaviors, Prader-Willi syndrome is a multisystem disorder with genetic, developmental, and behavioral features. Two separate and distinct eating disorders are noted: initial feeding difficulties and failure to thrive, and later overeating. Additional outcomes observed with this disorder include hypotonia, obesity, developmental/cognitive disabilities, and significant maladaptive behaviors. Symptoms vary in complexity across age and individuals. This necessitates multidisciplinary approaches to interventions across the life span to address medical, developmental, and behavioral issues. School psychologists have a vital role to play in assessment and consultation for individuals with this syndrome, their families, and school staff. (PsycINFO Database Record (c) 2010 APA, all rights reserved)     

Clinical features and molecular genetic analysis of a boy with Prader-Willi syndrome caused by an imprinting defect

Prader-Willi syndrome (PWS) is a neuroendocrine disorder caused by a non-functioning paternally derived gene(s) within the chromosome region 15q11-q13. Most cases result from microscopically visible deletions of paternal origin, or maternal uniparental disomy of chromosome 15. In both instances no recurrence has been reported. In rare cases, PWS is associated with lack of gene expression from the paternal allele due to an imprinting defect. We report the clinical features and the molecular genetic analysis of the first Danish child with PWS due to a defect of the putative imprinting centre (IC). When the imprinting mutation is inherited from a carrier father, the risk that future children will be affected is theoretically 50%. It is therefore important that these families are referred to a geneticist for counselling and further investigation. Prenatal diagnosis is currently only feasible when the mutation has been identified in the affected child.     

Problem behaviors associated with deletion Prader-Willi, Smith-Magenis, and cri du chat syndromes

Many studies have failed to determine a systematic dose-response relationship across different cognitive tasks between caffeine and EEG power spectra. However, a nonlinear approach to EEG analysis, which reconstructs a multi-dimensional state space from each electrode recording, can be used to compute the number of active degrees of freedom in the signal (the correlation dimension, D2), and can be interpreted as a measure of signal complexity. This study attempted to determine a consistent dose-response relationship between caffeine and EEG D2, across six oral caffeine doses (100-600 mg), with each subject acting as their own control, to create a probabilistic bias against finding any consistent linear or nonlinear dose-response relationship across different cognitive tasks. The experiment (n = 10) was conducted with three within-subjects explanatory variables, 2 (experimental, placebo) x 8 (caffeine level) x 4 (type of cognitive task performed), with EEG D2 as the response variable, measured from Fz, F3, F4 and Cz. A significant three-way interaction was found [F(21,245.3) = 3.65, P = 0.001]. Regression analyses revealed a linear trend for the response variable across trials for the placebo condition (average R2 = 0.54), whereas linear+quadratic trends explained an average 30% of the variance for the experimental condition, compared to 0.01% for the linear fit, indicating a robust quadratic dose-response relationship between caffeine and EEG D2. Three conditions had positive quadratic co-efficients, and one condition had a negative quadratic co-efficient. These results are discussed in terms of the implications for brain dynamics, and with respect to recent criticisms of the computation of D2 from EEG.     

Malignant potential, major histocompatibility complex antigen expression, and genomic imprinting of rat trophoblast cell lines

Invasive growth, variation in major histocompatibility complex antigen expression, and genomic imprinting are important properties of both trophoblast cells and malignant tumors. This study, undertaken to address these three issues, used cultured trophoblast cell lines derived from Day 11/12 rat placentas of all mating combinations of the DA and WF inbred strains. In addition, genomic imprinting was also examined in intact rat placentas from Days 11-19. There was no correlation in trophoblast cells between class I antigen expression, DNA content, and cell ploidy on the one hand and oncogenic potential on the other hand. The constitutive suppression of class II antigens in the trophoblast cells could not be abrogated by treatment with interferon-gamma, whereas such treatment always maximally induced class I antigen expression regardless of the initial resting levels. The trophoblast cells at Day 11/12 expressed both maternal and paternal class I antigens, and studies in whole placental tissues showed that the imprinting of the maternal class I antigens was manifested by a decreased level of expression rather than an absence of expression. Thus, genomic imprinting in the rat placenta is a quantitative, rather than an all-or-none, phenomenon.     

Evidence for a genomic imprinting sex determination mechanism in Nasonia vitripennis (Hymenoptera; Chalcidoidea)

HeT-A, a major component of Drosophila telomeres, is the first retrotransposon proposed to have a vital cellular function. Unlike most retrotransposons, more than half of its genome is noncoding. The 3' end contains > 2.5 kb of noncoding sequence. Copies of HeT-A differ by insertions or deletions and multiple nucleotide changes, which initially led us to conclude that HeT-A noncoding sequences are very fluid. However, we can now report, on the basis of new sequences and further analyses, that most of these differences are due to the existence of a small number of conserved sequence subfamilies, not to extensive sequence change during each transposition event. The high level of sequence conservation within subfamilies suggests that they arise from a small number of replicatively active elements. All HeT-A subfamilies show preservation of two intriguing features. First, segments of extremely A-rich sequence form a distinctive pattern within the 3' noncoding region. Second, there is a strong strand bias of nucleotide composition: The DNA strand running 5' to 3' toward the middle of the chromosome is unusually rich in adenine and unusually poor in guanine. Although not faced with the constraints of coding sequences, the HeT-A 3' noncoding sequence appears to be under other evolutionary constraints, possibly reflecting its roles in the telomeres.     

Within-event learning during filial imprinting.

Newly hatched domestic chicks that have received a period of exposure to a visual stimulus (V1) approach V1 in preference to a novel stimulus (V2). The learning process that underlies such changes in chicks' behavior is known as filial imprinting. Three experiments involving 208 chicks investigated the conditions that allow a potentiation of imprinting preferences to be observed. Under natural conditions, and in laboratory studies, V1 is often accompanied by an auditory stimulus, the maternal call of a hen (A1). Exps 1a and 1b demonstrated that simultaneous exposure to V1 and A1 potentiated Ss' preference for V1 in a test in which A1 was absent. Additional exposure to A1 after (Exp 2) or before (Exp 3) exposure to the V1A1 compound reduced the preference for V1. Findings suggest that the potentiation of visual imprinting is a product of within-event learning that is undermined when 1 element of the compound is presented in isolation. (PsycINFO Database Record (c) 2010 APA, all rights reserved)