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Prader–Willi syndrome (PWS) is a genetic disorder caused by a loss of function of specific genes on chromosome 15. In newborns, symptoms include weak muscles, poor feeding, and slow development. Beginning in childhood, those affected become constantly hungry, which often leads to obesity and type 2 diabetes. Mild to moderate intellectual impairment and behavioral problems are also typical of the disorder. Often, affected individuals have a narrow forehead, small hands and feet, short height, and light skin and hair. Most are unable to have children.
Chromosome 15q partial deletion is a rare human genetic disorder, caused by a chromosomal aberration in which the long ("q") arm of one copy of chromosome 15 is deleted, or partially deleted. Like other chromosomal disorders, this increases the risk of birth defects, developmental delay and learning difficulties, however, the problems that can develop depend very much on what genetic material is missing. If the mother's copy of the chromosomal region 15q11-13 is deleted, Angelman syndrome (AS) can result. The sister syndrome Prader-Willi syndrome (PWS) can result if the father's copy of the chromosomal region 15q11-13 is deleted. The smallest observed region that can result in these syndromes when deleted is therefore called the PWS/AS critical region. In addition to deletions, uniparental disomy of chromosome 15 also gives rise to the same genetic disorders, indicating that genomic imprinting must occur in this region.
Uniparental disomy (UPD) occurs when a person receives two copies of a chromosome, or of part of a chromosome, from one parent and no copy from the other. UPD can be the result of heterodisomy, in which a pair of non-identical chromosomes are inherited from one parent or isodisomy, in which a single chromosome from one parent is duplicated. Uniparental disomy may have clinical relevance for several reasons. For example, either isodisomy or heterodisomy can disrupt parent-specific genomic imprinting, resulting in imprinting disorders. Additionally, isodisomy leads to large blocks of homozygosity, which may lead to the uncovering of recessive genes, a similar phenomenon seen in inbred children of consanguineous partners.
Smith–Magenis Syndrome (SMS), also known as 17p- syndrome, is a microdeletion syndrome characterized by an abnormality in the short (p) arm of chromosome 17. It has features including intellectual disability, facial abnormalities, difficulty sleeping, and numerous behavioral problems such as self-harm. Smith–Magenis syndrome affects an estimated between 1 in 15,000 to 1 in 25,000 individuals.
Ubiquitin-protein ligase E3A (UBE3A) also known as E6AP ubiquitin-protein ligase (E6AP) is an enzyme that in humans is encoded by the UBE3A gene. This enzyme is involved in targeting proteins for degradation within cells.
Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 99.7 million base pairs and represents between 3% and 3.5% of the total DNA in cells. Chromosome 15 is an acrocentric chromosome, with a very small short arm, which contains few protein coding genes among its 19 million base pairs. It has a larger long arm that is gene rich, spanning about 83 million base pairs.
Topotecan, sold under the brand name Hycamtin among others, is a chemotherapeutic agent medication that is a topoisomerase inhibitor. It is a synthetic, water-soluble analog of the natural chemical compound camptothecin. It is used in the form of its hydrochloride salt to treat ovarian cancer, lung cancer and other cancer types.
Trisomic rescue is a genetic phenomenon in which a fertilized ovum containing three copies of a chromosome loses one of these chromosomes to form a diploid chromosome complement. If both of the retained chromosomes come from the same parent, then uniparental disomy results. If the retained chromosomes come from different parents then there are no phenotypic or genotypic anomalies. The mechanism of trisomic rescue has been well confirmed in vivo, and alternative mechanisms that occur in trisomies are rare in comparison.
Gamma-aminobutyric acid receptor subunit beta-3 is a protein that in humans is encoded by the GABRB3 gene. It is located within the 15q12 region in the human genome and spans 250kb. This gene includes 10 exons within its coding region. Due to alternative splicing, the gene codes for many protein isoforms, all being subunits in the GABAA receptor, a ligand-gated ion channel. The beta-3 subunit is expressed at different levels within the cerebral cortex, hippocampus, cerebellum, thalamus, olivary body and piriform cortex of the brain at different points of development and maturity. GABRB3 deficiencies are implicated in many human neurodevelopmental disorders and syndromes such as Angelman syndrome, Prader-Willi syndrome, nonsyndromic orofacial clefts, epilepsy and autism. The effects of methaqualone and etomidate are mediated through GABBR3 positive allosteric modulation.
Marcus Edred Pembrey FMedSci is a British clinical geneticist with a research interest in non-Mendelian inheritance in humans. He is Emeritus Professor of Paediatric Genetics at UCL Great Ormond Street Institute of Child Health and Visiting Professor of Paediatric Genetics, University of Bristol. He featured in a 2005 'Horizon' program on BBC television called 'the Ghost in Your Genes'.
Small nuclear ribonucleoprotein-associated protein N is a protein that in humans is encoded by the SNRPN gene.
SNRPN upstream reading frame protein is a protein that in humans is encoded by the SNURF gene.
Angelman syndrome or Angelman's syndrome (AS) is a genetic disorder that mainly affects the nervous system. Symptoms include a small head and a specific facial appearance, severe intellectual disability, developmental disability, limited to no functional speech, balance and movement problems, seizures, and sleep problems. Children usually have a happy personality and have a particular interest in water. The symptoms generally become noticeable by one year of age.
In molecular biology, Small nucleolar RNA SNORD113 is a small nucleolar RNA molecule which is located in the imprinted human 14q32 locus and may play a role in the evolution and/or mechanism of the epigenetic imprinting process.
Potocki–Lupski syndrome (PTLS), also known as dup(17)p11.2p11.2 syndrome, trisomy 17p11.2 or duplication 17p11.2 syndrome, is a contiguous gene syndrome involving the microduplication of band 11.2 on the short arm of human chromosome 17 (17p11.2). The duplication was first described as a case study in 1996. In 2000, the first study of the disease was released, and in 2007, enough patients had been gathered to complete a comprehensive study and give it a detailed clinical description. PTLS is named for two researchers involved in the latter phases, Drs. Lorraine Potocki and James R. Lupski of Baylor College of Medicine.
Genomic structural variation is the variation in structure of an organism's chromosome. It consists of many kinds of variation in the genome of one species, and usually includes microscopic and submicroscopic types, such as deletions, duplications, copy-number variants, insertions, inversions and translocations. Originally, a structure variation affects a sequence length about 1kb to 3Mb, which is larger than SNPs and smaller than chromosome abnormality. However, the operational range of structural variants has widened to include events > 50bp. The definition of structural variation does not imply anything about frequency or phenotypical effects. Many structural variants are associated with genetic diseases, however many are not. Recent research about SVs indicates that SVs are more difficult to detect than SNPs. Approximately 13% of the human genome is defined as structurally variant in the normal population, and there are at least 240 genes that exist as homozygous deletion polymorphisms in human populations, suggesting these genes are dispensable in humans. Rapidly accumulating evidence indicates that structural variations can comprise millions of nucleotides of heterogeneity within every genome, and are likely to make an important contribution to human diversity and disease susceptibility.
UBE3A-ATS/Ube3a-ATS (human/mouse), otherwise known as ubiquitin ligase E3A-ATS, is the name for the antisense DNA strand that is transcribed as part of a larger transcript called LNCAT at the Ube3a locus. The Ube3a locus is imprinted and in the central nervous system expressed only from the maternal allele. Silencing of Ube3a on the paternal allele is thought to occur through the Ube3a-ATS part of LNCAT, since non-coding antisense transcripts are often found at imprinted loci. The deletion and/or mutation of Ube3a on the maternal chromosome causes Angelman Syndrome (AS) and Ube3a-ATS may prove to be an important aspect in finding a therapy for this disease. While in patients with AS the maternal Ube3a allele is inactive, the paternal allele is intact but epigenetically silenced. If unsilenced, the paternal allele could be a source of active Ube3a protein in AS patients. Therefore, understanding the mechanisms of how Ube3a-ATS might be involved in silencing the paternal Ube3a may lead to new therapies for AS. This possibility has been demonstrated by a recent study where the drug topotecan, administered to mice suffering from AS, activated expression of the paternal Ube3a gene by lowering the transcription of Ube3a-ATS.
Autism spectrum disorder (ASD) refers to a variety of conditions typically identified by challenges with social skills, communication, speech, and repetitive sensory-motor behaviors. The 11th International Classification of Diseases (ICD-11), released in January 2021, characterizes ASD by the associated deficits in the ability to initiate and sustain two-way social communication and restricted or repetitive behavior unusual for the individual's age or situation. Although linked with early childhood, the symptoms can appear later as well. Symptoms can be detected before the age of two and experienced practitioners can give a reliable diagnosis by that age. However, official diagnosis may not occur until much older, even well into adulthood. There is a large degree of variation in how much support a person with ASD needs in day-to-day life. This can be classified by a further diagnosis of ASD level 1, level 2, or level 3. Of these, ASD level 3 describes people requiring very substantial support and who experience more severe symptoms. ASD-related deficits in nonverbal and verbal social skills can result in impediments in personal, family, social, educational, and occupational situations. This disorder tends to have a strong correlation with genetics along with other factors. More research is identifying ways in which epigenetics is linked to autism. Epigenetics generally refers to the ways in which chromatin structure is altered to affect gene expression. Mechanisms such as cytosine regulation and post-translational modifications of histones. Of the 215 genes contributing, to some extent in ASD, 42 have been found to be involved in epigenetic modification of gene expression. Some examples of ASD signs are specific or repeated behaviors, enhanced sensitivity to materials, being upset by changes in routine, appearing to show reduced interest in others, avoiding eye contact and limitations in social situations, as well as verbal communication. When social interaction becomes more important, some whose condition might have been overlooked suffer social and other exclusion and are more likely to have coexisting mental and physical conditions. Long-term problems include difficulties in daily living such as managing schedules, hypersensitivities, initiating and sustaining relationships, and maintaining jobs.
Chromosomal deletion syndromes result from deletion of parts of chromosomes. Depending on the location, size, and whom the deletion is inherited from, there are a few known different variations of chromosome deletions. Chromosomal deletion syndromes typically involve larger deletions that are visible using karyotyping techniques. Smaller deletions result in Microdeletion syndrome, which are detected using fluorescence in situ hybridization (FISH)
A microdeletion syndrome is a syndrome caused by a chromosomal deletion smaller than 5 million base pairs spanning several genes that is too small to be detected by conventional cytogenetic methods or high resolution karyotyping. Detection is done by fluorescence in situ hybridization (FISH). Larger chromosomal deletion syndromes are detectable using karyotyping techniques.
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- ↑ Sahoo, T; del Gaudio, D; German, JR; Shinawi, M; Peters, SU; Person, RE; Garnica, A; Cheung, SW; Beaudet, AL (June 2008). "Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster". Nature Genetics. 40 (6): 719–21. doi:10.1038/ng.158. PMC 2705197 . PMID 18500341.
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