Genomic imprinting and candidate genes in the Prader-Willi and Angelman syndromes

doi:10.1016/0959-437X(93)90119-A

Current Opinion in Genetics & Development

Volume 3, Issue 3, June 1993, Pages 445-456

https://doi.org/10.1016/0959-437X(93)90119-A Get rights and content

Abstract

The Prader-Willi and Angelman syndromes are now well established as the paradigm of genomic imprinting in human disease. Over the past year, much has been learnt about the mechanisms by which these syndromes arise and molecular diagnostics for the majority of patients are now available. Mouse models for aspects of the syndromes have been established, and the first association between a genem located in chromosome 15, at 15q11-q13, and a phenotype (albinism) has been proven. Large parts of the critical regions have been cloned and at least six genes identified. Three genes or DNA sequences may be imprinted: two of these demonstrate DNA-methylation imprints and one is functionally imprinted in mouse. While the molecular mechanism of imprinting is not yet understood, it is beginning to yield its secrets to DNA methylation, replication, and chromatin structure studies of the phenomenon.

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Cited by (77)

Case of 15q26-qter deletion associated with a Prader-Willi phenotype
2020, European Journal of Medical Genetics
Citation Excerpt :
Thank you.ernally inherited genes in the 15q11.2-q13 region. The causes are paternal microdeletion in 70% of cases, maternal uniparentaldisomy (UPD) in 20–30% of cases, and maternal imprinting defect in 1% (Dagli et al., 1998 Sep 15 [Updated, 2015 May 14]; Mutirangura et al., 1993; Nicholls, 1993, 2000). The syndrome is characterized principally by severe neonatal hypotonia, with a weak suck that is followed by hyperphagia and obesity from 6 years of age onwards, developmental delay, intellectual disability, short stature, hypogonadism and behavioral disturbances (Butler, 2011; Jin, 2011).
Prader-Willi syndrome (PWS) is one of the common neurogenetic disorders associated with intellectual disability. PWS involves a complex inheritance pattern and is caused by an absence of gene expression on the paternally inherited 15q11.2-q13 region, either due to deletion, maternal uniparental disomy or imprinting defect. The syndrome is characterized principally by severe neonatal hypotonia, a weak suck in infancy that is later followed by hyperphagia and obesity, developmental delay, intellectual disability and short stature. In the case of the chromosome 15q26-qter deletion syndrome or Drayer's syndrome, very few reports have been published. Its characteristics include intrauterine growth restriction, postnatal growth failure, varying degrees of intellectual disability, developmental delay, typical facial appearance and diaphragmatic hernia. The present paper describes a female patient in whom clinical findings were suggestive of PWS and deletion in the 15q26-qter region. Both karyotyping and methylation-specific polymerase chain reaction were shown to be normal. Nevertheless, fluorescence in situ hybridization showed a 15qter deletion that was later mapped by single nucleotide polymorphism (SNP)-array. The deleted genomic region involves the insulin-like growth factor-1 receptor (IGF1R) gene, which is related to short stature, developmental delay and intellectual disability. This case had various clinical characteristics in common with the cases of 15q26-qter deletionand characteristics compatible with PWS.
The comorbidity of autism with the genomic disorders of chromosome 15q11.2-q13
2010, Neurobiology of Disease
Citation Excerpt :
GABA, the major inhibitory neurotransmitter in the brain, functions to hyperpolarize the membrane through binding to ionotropic pentameric GABAA receptors. Chromosome 15q11.2-q13 contains three GABAA receptor subunit genes (GABR), GABRB3, GABRA5, and GABRG3 that are normally biallelically expressed in mouse and human (Buettner et al., 2004; Hogart et al., 2007; Nicholls, 1993). Although the 15q11.2-q13 GABR genes are not imprinted, the increased severity of PWS and AS deletion patients compared to UPD patients (Varela et al., 2004, 2005) implicates a role for GABR genes in these disorders.
A cluster of low copy repeats on the proximal long arm of chromosome 15 mediates various forms of stereotyped deletions and duplication events that cause a group of neurodevelopmental disorders that are associated with autism or autism spectrum disorders (ASD). The region is subject to genomic imprinting and the behavioral phenotypes associated with the chromosome 15q11.2-q13 disorders show a parent-of-origin specific effect that suggests that an increased copy number of maternally derived alleles contributes to autism susceptibility. Notably, nonimprinted, biallelically expressed genes within the interval also have been shown to be misexpressed in brains of patients with chromosome 15q11.2-q13 genomic disorders, indicating that they also likely play a role in the phenotypic outcome. This review provides an overview of the phenotypes of these disorders and their relationships with ASD and outlines the regional genes that may contribute to the autism susceptibility imparted by copy number variation of the region.
On the origin of sensory impairment and altered pain perception in Prader-Willi syndrome: A neurophysiological study
2009, European Journal of Pain
Citation Excerpt :
Prader–Willi syndrome (PWS) affects both sexes, all races, and one in 22,000–27,000 live births (Butler et al., 2002; Vogels et al., 2004). The genetic basis is a deletion of the paternally derived chromosome 15 (del15q11–13) or maternal uniparental disomy (UPD) for chromosome 15 in the majority of cases (Cassidy et al., 1997; Nicholls, 1993). Other rare genetic defects can occur (Khan and Wood, 1999).
High pain threshold is a supportive diagnosis criterion for Prader–Willi syndrome (PWS), but its pathogenesis is poorly understood. In this study we investigate sensory pathways in PWS, in order to evaluate peripheral or central involvement in altered sensory perception.
14 adult PWS patients, 10 obese non-diabetic people and 10 age-matched controls underwent: (a) motor/sensory nerve conduction velocities at the upper and lower limbs; (b) palmar/plantar sympathetic skin response; (c) somatosensory evoked potentials from upper/lower limbs; (d) quantitative sensory testing to measure sensory threshold for vibration, warm and cold sensation, heat and cold-induced pain and (e) blood sample analysis to evaluate glucose and insulin levels and to calculate the quantitative insulin-sensitivity check index (QUICKI).
Electroneurographic examination, sympathetic skin response and somatosensory evoked potentials were all within normal ranges. In the PWS group, thermal and pain thresholds but not vibratory were significantly higher than in healthy and obese people (p < 0.05). Sensory threshold did not correlate with BMI nor with QUICKI.
Our data suggest that altered perception in PWS does not seem attributable to a peripheral nerve derangement due to metabolic factors or obesity. Impairment of the small nociceptive neurons of dorsal root ganglia or involvement of hypothalamic region may not be excluded.
Molecular links between X-inactivation and autosomal imprinting: X-inactivation as a driving force for the evolution of imprinting?
2003, Current Biology
Citation Excerpt :
Evidence for an ICR first emerged in the Prader-Willi and Angelman Syndromes loci, two developmental disorders long noted to be opposite in phenotype – for example, lethargy in PWS and hyperactivity in AS – which were mapped to contiguous, if not identical, regions of human chromosome 15. Studies in the 1990s led to the identification of several patients with so-called ‘imprinting defects’ in which deleting a 4 megabase domain including 2–3 megabases of imprinted genes within the PWS/AS locus led to a switch from a maternal to a paternal epigenotype or vice versa[76]. It is presently believed that the PWS/AS imprinting center lies in a 25–30 kilobase region and is composed of two elements: an 880 base-pair AS center 35 kilobase upstream of the Snrpn gene; and a 4.3 kilobase PWS center at the 5′ end of the Snrpn gene [35].
In classical Mendelian inheritance, each parent donates a set of chromosomes to its offspring so that maternally and paternally encoded information is expressed equally. The phenomena of X-chromosome inactivation (XCI) and autosomal imprinting in mammals violate this dogma of genetic equality. In XCI, one of the two female X chromosomes is silenced to equalize X-linked gene dosage between XX and XY individuals. In genomic imprinting, parental marks determine which of the embryo's two autosomal alleles will be expressed. Although XCI and imprinting appear distinct, molecular evidence now shows that they share a surprising number of features. Among them are cis-acting control centers, long-distance regulation and differential DNA methylation. Perhaps one of the most intriguing similarities between XCI and imprinting has been their association with noncoding and antisense RNAs. Very recent data also suggest the common involvement of histone modifications and chromatin-associated factors such as CTCF. Collectively, the evidence suggests that XCI and genomic imprinting may have a common origin. Here, I hypothesize that the need for X-linked dosage compensation was a major driving force in the evolution of genomic imprinting in mammals. I propose that imprinting was first fixed on the X chromosome for XCI and subsequently acquired by autosomes.
Analysis of the methylation status of imprinted genes based on methylation-specific polymerase chain reaction combined with denaturing high-performance liquid chromatography
2002, Methods
A procedure for the analysis of the methylation status of imprinted genes is described. The method offers a rapid and reliable alternative to conventional methods such as Southern blots and methylation-specific polymerase chain reaction (PCR) (i.e., allele-specific methylation-specific PCR). The efficient resolution of the differentially methylated alleles is demonstrated for three human imprinted genes: SNRPN, LIT1 (alias KCNQ1OT1), and H19. Abnormal imprinting of SNRPN is associated with the Angelman/Prader–Willi syndromes, and that of LIT1 and H19 with the Beckwith–Wiedemann syndrome. The method is based on methylation-specific PCR followed by denaturing high-performance liquid chromatography (MSP/DHPLC). Briefly, genomic DNA is initially subjected to an in vitro bisulfite treatment, whereby unmethylated cytosines are deaminated. Subsequent PCR amplifications, using primers specific for modified DNA, are aimed at DNA segments that show parent-of-origin-specific methylation. PCR conditions are chosen that allow an efficient amplification of both alleles. The PCR products representing the two alleles are identical in size; they differ, however, at a number of positions within the amplified DNA segment. The DHPLC analysis allows very efficient resolution of the two populations of PCR products, providing qualitative and quantitative results.
Genetic linkage of IgA deficiency to the major histocompatibility complex: Evidence for allele segregation distortion parent-of-origin penetrance differences, and the role of anti-IgA antibodies in disease predisposition
1999, American Journal of Human Genetics
Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic susceptibility to IgAD is shared with a less prevalent, but more profound, defect called “common variable immunodeficiency” (CVID). Here we show an increased allele sharing at 6p21 in affected members of 83 multiplex IgAD/CVID pedigrees and demonstrate, using transmission/diseqilibrium tests, family-based associations indicating the presence of a predisposing locus, designated “IGAD1,” in the proximal part of the major histocompatibility complex (MHC). The recurrence risk of IgAD was found to depend on the sex of parents transmitting the defect: affected mothers were more likely to produce offspring with IgAD than were affected fathers. Carrier mothers but not carrier fathers transmitted IGAD1 alleles more frequently to the affected offspring than would be expected under random segregation. The differential parent-of-origin penetrance is proposed to reflect a maternal effect mediated by the production of anti-IgA antibodies tentatively linked to IGAD1. This is supported by higher frequency of anti-IgA–positive females transmitting the disorder to children, in comparison with female IgAD nontransmitters, and by linkage data in the former group. Such pathogenic mechanisms may be shared by other MHC-linked complex traits associated with the production of specific autoantibodies, parental effects, and a particular MHC haplotype.

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Genomic imprinting and candidate genes in the Prader-Willi and Angelman syndromes

Abstract

Lancet

J Med Genet

Cell

Prader-Willi Syndrome: Consensus Diagnostic Criteria

Pediatrics

Angelman Syndrome

J Med Genet

Genomic Imprinting and Uniparental Disomy in Angelam and Prader-Willi Syndrome: A Review

Am J Med Genet

Genomic Imprinting in Mammalian Development: Prader-Willi and Angelman Syndromes as Disease Models

Angelman Syndrome: Three Molecular Classes Identified with Chromosome 15q11-q13 specific DNA Markers

Am J Hum Genet

Comparison of the 15q Deletions in Prader-Willi and Angelman Syndromes: Specific Regions, Extent of Deletions, Parental Origin, and Clinical Consequences

Am J Med Genet

Molecular, Cytogenetic, and Clinical Investigations of Prader-Willi Syndrome Patients

Am J Hum Genet

The Frequency of Uniparental Disomy in Prader-Willi Syndrome: Implications for Molecular Diagnosis

New Engl J Med

Parental Uniparental Disomy of Chromosome 15 in a Child with Angelman Syndrome

Ann Neurol

Multiplex PCR of Three Dinucleotide Repeats in the Prader-Willi/Angelman Critical Region (15q11-q13): Molecular Diagnosis and Mechanism of Uniparental Disomy

Hum Mol Genet

Trisomy 15 with Loss of the Paternal 15 as a Cause of Prader-Willi Syndrome Due to Maternal Disomy

Am J Hum Genet

Prader-Willi and Angelman Syndrome in Cousins from a Family with a Translocation between Chromosomes 6 and 15

New Engl J Med

A Gene for the Mouse Pink-eyed Dilution Locus and for Human Type II Oculocutaneous Albinism

Nature

Maternal but not Paternal Transmission of 15q11-q13-linked Nondeletion Angelman Syndrome Leads to Phenotypic Expression

Nature Genet

Ordering of Reference Markers by FISH and Assignment of the Gene for the α5 Subunit of the γ-Aminobutyric Acid Receptor within the Angelman and Prader-Willi Chromosomal Regions

Hum Mol Genet

Molecular Dissection of the Prader-Willi/Angelman Syndrome Region (15q11–13) by YAC Cloning and FISH Analysis

Hum Mol Genet

A DNA Methylation Impring, Determined by the Sex of the Parent, Distinguishes the Angelman and Prader-Willi Syndromes

Genomics

Molecular Diagnosis of the Prader-Willi and Angelman Syndromes by Detection of Parent-of-origin Specific DNA Methylation in 15q11-q13

Hum Genet

Further Evidence for Dominant Inheritance at the Chromosome 15q11-q13 Locus in Familial Angelman Syndrome

Am J Med Genet

Localization of the Gene Encoding the GABAA Receptor β3 Subunit to the Angelman/Prader-Willi Region of Human Chromosome 15

Am J Hum Genet

Localization of the Gene Encoding the GABA_A Receptor β3 Subunit to the Angelman/Prader-Willi Region of Human Chromosome 15