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Molecular genetics and animal models in autistic disorder.

Autistic disorder is a behavioural syndrome beginning before the age of 3 years and lasting over the whole lifetime. It is characterised by impaired communication, impaired social interactions, and repetitive interests and behaviour. The prevalence is about 7/10,000 taking a restrictive definition and more than 1/500 with a broader definition, including all the pervasive developmental disorders. The importance of genetic factors has been highlighted by epidemiological studies showing that autistic disorder is one of the most genetic neuropsychiatric diseases. The relative risk of first relativ

[Autism, chromosome 15 and the GAbaergic dysfunction hypothesis].

Autism is a complex neurodevelopmental disorder characterized by impairment of social interaction, language, communication, and stereotyped, repetitive behavior. Genetic predisposition to autism has been demonstrated from families and twin studies. Despite recent advances in identifying some susceptibility candidate genes, its underlying neurological mechanism is uncertain. There are genetic, biochemical and neuropathological findings that support the hypothesis that autism could be caused by GABAergic dysfunction and it is partially responsible for the etiology of this disorder. One of the mo

α6-Containing GABAA Receptors: Functional Roles and Therapeutic Potentials.

GABAA receptors containing the α6 subunit are highly expressed in cerebellar granule cells and less abundantly in many other neuronal and peripheral tissues. Here, we for the first time summarize their importance for the functions of the cerebellum and the nervous system. The cerebellum is not only involved in motor control but also in cognitive, emotional, and social behaviors. α6βγ2 GABAA receptors located at cerebellar Golgi cell/granule cell synapses enhance the precision of inputs required for cerebellar timing of motor activity and are thus involved in cognitive processing and adequate r

Geriatric palliative care: clinical imperatives, ethical challenges and public health opportunities.

It is estimated that Angelman syndrome (AS) accounts for up to 6% of all children presenting with severe mental retardation and epilepsy. The main clinical features of AS may not be apparent early in life. Clinical findings present in all patients include developmental delay, which becomes apparent by 6-12 months of age, severely impaired expressive language, ataxic gait, tremulousness of limbs, and a typical behavioral profile, including a happy demeanor, hypermotoric behavior, and low attention span. Seizures, abnormal electroencephalography, microcephaly, and scoliosis are observed in >80% …

Genomic analysis of the chromosome 15q11-q13 Prader-Willi syndrome region and characterization of transcripts for GOLGA8E and WHCD1L1 from the proximal breakpoint region.

BACKGROUND: Prader-Willi syndrome (PWS) is a neurobehavioral disorder characterized by neonatal hypotonia, childhood obesity, dysmorphic features, hypogonadism, mental retardation, and behavioral problems. Although PWS is most often caused by a paternal interstitial deletion of a 6-Mb region of chromosome 15q11-q13, the identity of the exact protein coding or noncoding RNAs whose deficiency produces the PWS phenotype is uncertain. There are also reports describing a PWS-like phenotype in a subset of patients with full mutations in the FMR1 (fragile X mental retardation 1) gene. Taking advantag

Exogenous melatonin for sleep problems in individuals with intellectual disability: a meta-analysis.

Recent meta-analyses on melatonin has raised doubts as to whether melatonin is effective in treating sleep problems in people without intellectual disabilities. This is in contrast to results of several trials on melatonin in treating sleep problems in individuals with intellectual disabilities. To investigate the efficacy of melatonin in treating sleep problems in individuals with intellectual disabilities, we performed a meta-analysis of placebo-controlled randomized trials of melatonin in individuals with intellectual disabilities and sleep problems. Data were selected from articles publish

[Detection of subtelomeric rearrangements in patients with idiopathic mental retardation/developmental delay].

OBJECTIVE: To detect subtelomeric rearrangement in patients with idiopathic mental retardation/developmental delays (MR/DD) and to provide n … ible for the mental retardation phenotype of these patients. The phenotype of case 4 was similar to Angelman syndrome, his deletion was actually a kind of interstitial rearrangements. It will be confirmed by DNA methylation test to determine whether the deleted allele was of maternal origin. CONCLUSIONS: The subtelomeric rearrangements were found in 10% patients w …

Population-Based Risk of Psychiatric Disorders Associated With Recurrent Copy Number Variants.

IMPORTANCE: Recurrent copy number variants (rCNVs) have been associated with increased risk of psychiatric disorders in case-control studies … oss these disorders. Notable exceptions included high ASD-associated risk observed for Prader-Willi/Angelman syndrome duplications (HR, 20.8; 95% CI, 7.9-55). No rCNV was associated with increased MDD risk. Also, rCNV-associated risk was positively correlated with locus size and gene constraint but not with dosage type. Comparison with published case-control and co …

Multiplex ligation-dependent probe amplification for genetic screening in autism spectrum disorders: efficient identification of known microduplications and identification of a novel microduplication in ASMT.

BACKGROUND: It has previously been shown that specific microdeletions and microduplications, many of which also associated with cognitive impairment (CI), can present with autism spectrum disorders (ASDs). Multiplex ligation-dependent probe amplification (MLPA) represents an efficient method to screen for such recurrent microdeletions and microduplications. METHODS: In the current study, a total of 279 unrelated subjects ascertained for ASDs were screened for genomic disorders associated with CI using MLPA. Fluorescence in situ hybridization (FISH), quantitative polymerase chain reaction (Q-P

Imprinting of the mouse Igf2r gene depends on an intronic CpG island.

Gametic imprinting is a developmental process that uses cis-acting epigenetic mechanisms to induce parental-specific expression in autosomal … from gene deletion experiments in the mouse and the analysis of deletions in the human Prader-Willi/Angelman syndromes that imprinted genes are also influenced by distant DNA sequences. We have earlier proposed that CG rich sequences resembling CpG islands, which are associated with many imprinted genes and often subject to parental-specific methylation, could act …

A brief clinical genetics review: stepwise diagnostic processes of a monogenic disorder-hypertriglyceridemia.

The completion of the Human Genome Project and tremendous advances in automated high-throughput genetic analysis technologies have enabled explosive progress in the field of genetics, which resulted in countless discoveries of novel genes and pathways. Many phenotype- or disease-associated single nucleotide polymorphisms (SNPs) with a high statistical significance have been identified through numerous genome-wide association studies (GWAS), and various polygenic risk scoring (PRS) schemes have been proposed to identify individuals with a high risk for a certain trait or disorder. Meanwhile, me

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… syndrome ‡ Uniparental isodisomy † (including DMR † ) | Meiosis II error † , post-zygotic chromosomal duplication | Two identical chromosomes with DMR from one parent | Prader-Willi syndrome Angelman syndrome Imprinting disorders † | Abnormalities at DMR | Abnormal expressions of genes in DMR | Prader-Wcyndrome … Prader-Willi and Angelman syndromes are great examples that display these unique properties of DMRs. A methylation analysis is the initial genetic test commonly recommended for imprinting disorders ( 19 ). …

Pregnancy outcomes after assisted human reproduction.

OBJECTIVE: To review the effect of assisted human reproduction (AHR) on perinatal outcomes, to identify areas requiring further research wit … e risk for an imprinting phenotype such as Silver-Russell syndrome, Beckwith-Wiedemann syndrome, or Angelman syndrome is increased in the assisted reproduction population, but the actual risk for one of these phenotypes to occur in an assisted pregnancy is estimated to be low, at less than 1 in 5000. The exact biological etiology for this increased imprinting risk …

Сексуальные отношения с лицами, страдающими расстройством бдительности: обзор.

Целью этого обзора повествования является проведение синтетического обзора современных знаний о взаимосвязи между расстройством гиперактивности (АДХД) и сексуальным функционированием взрослых с уделением особого внимания нейробиологическим механизмам, коморбидным расстройствам и воздействию фармакотерапии. Шесть независимых исследователей провели всеобъемлющий обзор литературы с использованием баз данных PubMed, Scopus и Google Scientist, охватывающих публикации, имеющиеся по состоянию на май 2024 года. Были включены первоначальные исследовательские документы, обзоры и метаанализы на английско

Drugs and Epigenetic Molecular Functions. A Pharmacological Data Scientometric Analysis.

Interactions of drugs with the classical epigenetic mechanism of DNA methylation or histone modification are increasingly being elucidated mechanistically and used to develop novel classes of epigenetic therapeutics. A data science approach is used to synthesize current knowledge on the pharmacological implications of epigenetic regulation of gene expression. Computer-aided knowledge discovery for epigenetic implications of current approved or investigational drugs was performed by querying information from multiple publicly available gold-standard sources to (i) identify enzymes involved in c

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… However, first human studies of the treatment of the Angelman syndrome have started in 2020 ( https://clinicaltrials.gov/search/term=Angelman%20Syndrome ). …

Геномический диагноз детских расстройств: революция и эволюция.

Мощные, последние достижения в технологиях анализа генома оказали глубокое воздействие на практику медицинской генетики как в лаборатории, так и в клинике. Более широкое использование общегеномных тестов, таких, как анализ хромосомных микроарра и последовательность экзомов, привело к переходу к "генотипному" подходу. В настоящее время имеются многочисленные методы диагностики конкретного синдрома или фенотипа, и, хотя традиционные методы остаются эффективными инструментами в некоторых ситуациях, технологии с более высокой производительностью фактически стали лабораторным инструментом диагности

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… Clinical Examples Prader-Willi syndrome (PWS) and Angelman syndrome (AS) PWS and AS result from imprinting abnormalities at 15q11.2-q13 and illustrate how disruption of imprinting patterns on either the maternal or paternal allele result in distinct diseases. …

Inhibition of Cxcr4 chemokine receptor signaling improves habituation learning in a zebrafish model of neurofibromatosis.

Neurofibromatosis type 1 (NF1) is a neurogenetic disorder caused by loss-of-function mutations in the gene neurofibromin 1 (NF1). NF1 encodes neurofibromin, a multifunctional tumor-suppressing protein that regulates Ras, cAMP and dopamine signaling. NF1 predisposes patients to a wide range of symptoms, including peripheral nerve tumors, brain tumors and cognitive dysfunction. Despite considerable work using animal models to investigate the role of neurofibromin in behavior, translating research into treatment for NF1-associated cognitive dysfunction has not yet been successful. Here, we provid

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… However, topoisomerase inhibitors can activate epigenetically silenced ubiquitin protein ligase alleles in neurons associated with Angelman syndrome ( Huang et al., 2011 ), and mouse models for Angelman syndrome display deficits in acoustic startle and PPI ( Huang et al., 2013 ). … Behavioral deficits in an Angelman syndrome model: effects of genetic background and age . Behav. Brain Res. 243 , 79 - 90 . 10.1016/j.bbr.2012.12.052 23295389 PMC3629944 Huson , S. M. , Compston , D. A. and Harper , P. S. ( 1989 ). …

Генетическая основа болезни.

Генетика в той или иной степени играет определенную роль во всех заболеваниях. Изменения в нашей ДНК и различия в том, как эта ДНК функционирует (одиночка или комбинация), наряду с окружающей средой (которая включает образ жизни), способствуют болезнетворным процессам. В рамках этого обзора изучается генетическая основа человеческих заболеваний, включая однородные генетические расстройства, хромосомные диспропорции, эпигенетические, раковые и сложные расстройства, и рассматривается вопрос о том, каким образом наше понимание и технологические достижения могут быть использованы для обеспечения н

Ubiquitylomics: An Emerging Approach for Profiling Protein Ubiquitylation in Skeletal Muscle.

Skeletal muscle is a highly adaptable tissue, finely tuned by various physiological and pathological factors. Whilst the pivotal role of skeletal muscle in overall health is widely acknowledged, unravelling the underlying molecular mechanisms poses ongoing challenges. Protein ubiquitylation, a crucial post-translational modification, is involved in regulating most biological processes. This widespread impact is achieved through a diverse set of enzymes capable of generating structurally and functionally distinct ubiquitin modifications on proteins. The complexity of protein ubiquitylation has

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… For instance, lack of the DUB Uchl1 in Gracile Axonal Dystrophy (GAD) impairs the synaptic transmission at neuromuscular junctions, loss of function in the E3 ligase coding gene Ube3a disrupts proteasome activity in Angelman Syndrome (AS), the E3 ligase Rnf126 degrades frataxin which is reduced in Friedreich … Tomaić V. and Banks L., “Angelman Syndrome‐Associated Ubiquitin Ligase UBE3A/E6AP Mutants Interfere With the Proteolytic Activity of the Proteasome,” Cell Death & Disease 6, no. 1 (2015): e1625. 92. …

Ubiquitin-specific peptidases in lymphoma: a path to novel therapeutics.

BackgroundUbiquitin-specific peptidases (USPs), also known as deubiquitinating enzymes (DUBs), play a crucial role in maintaining cellular homeostasis by selectively removing ubiquitin molecules from targeted proteins. This process affects protein stability, subcellular localization, and activity, thereby influencing processes such as DNA repair, cell cycle regulation, and apoptosis. Abnormal USP activities have been linked to various diseases, including cancer. Emerging evidence in lymphoma studies highlights the significance of USPs in controlling signaling pathways related to cancer initiat

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… The ubiquitin–protease system (UPS) is likely involved in human brain development since a defect in the gene encoding the E3 ligase E6-AP has been directly implicated in the cause of Angelman syndrome. …

Cancer and Obesity: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2022.

BackgroundThis Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) provides an overview of cancer and increased body fat.MethodsThe scientific information for this CPS is based upon published scientific citations, clinical perspectives of OMA authors, and peer review by the Obesity Medicine Association leadership.ResultsTopics include the increased risk of cancers among patients with obesity, cancer risk factor population-attributable fractions, genetic and epigenetic links between obesity and cancer, adiposopathic and mechanistic processes accounting for increased cancer risk

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… Imprinting in prader-willi and angelman syndromes. Trends Genet : TIG (Trends Genet) 1998;14:194–200. doi: 10.1016/s0168-9525(98)01432-2. 41. Bays H., Scinta W. Adiposopathy and epigenetics: an introduction to obesity as a transgenerational disease. …