International Journal of Molecular Sciences

Research

24 pages, 1001 KiB

Open AccessArticle

by Liza Weinstein-Fudim, Zivanit Ergaz, Gadi Turgeman, Joseph Yanai, Moshe Szyf and Asher Ornoy

Int. J. Mol. Sci. 2019, 20(21), 5278; https://doi.org/10.3390/ijms20215278 - 24 Oct 2019

Cited by 21 | Viewed by 4075

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology [...] Read more.

In previous studies we produced autism like behavioral changes in mice by Valproic acid (VPA) with significant differences between genders. S-adenosine methionine (SAM) prevented the autism like behavior in both genders. The expression of 770 genes of pathways involved in neurophysiology and neuropathology was studied in the prefrontal cortex of 60 days old male and female mice using the NanoString nCounter. In females, VPA induced statistically significant changes in the expression of 146 genes; 71 genes were upregulated and 75 downregulated. In males, VPA changed the expression of only 19 genes, 16 were upregulated and 3 downregulated. Eight genes were similarly changed in both genders. When considering only the genes that were changed by at least 50%, VPA changed the expression of 15 genes in females and 3 in males. Only Nts was similarly downregulated in both genders. SAM normalized the expression of most changed genes in both genders. We presume that genes that are involved in autism like behavior in our model were similarly changed in both genders and corrected by SAM. The behavioral and other differences between genders may be related to genes that were differently affected by VPA in males and females and/or differently affected by SAM. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

22 pages, 284 KiB

Open AccessArticle

Associations between Monocyte and T Cell Cytokine Profiles in Autism Spectrum Disorders: Effects of Dysregulated Innate Immune Responses on Adaptive Responses to Recall Antigens in a Subset of ASD Children

by Harumi Jyonouchi and Lee Geng

Int. J. Mol. Sci. 2019, 20(19), 4731; https://doi.org/10.3390/ijms20194731 - 24 Sep 2019

Cited by 19 | Viewed by 3062

Abstract

Changes in monocyte cytokine production with toll like receptor (TLR) agonists in subjects with autism spectrum disorders (ASD) were best reflected by the IL-1β/IL-10 ratios in our previous research. The IL-1β/IL-10 based subgrouping (low, normal, and high) of ASD samples revealed marked differences [...] Read more.

Changes in monocyte cytokine production with toll like receptor (TLR) agonists in subjects with autism spectrum disorders (ASD) were best reflected by the IL-1β/IL-10 ratios in our previous research. The IL-1β/IL-10 based subgrouping (low, normal, and high) of ASD samples revealed marked differences in microRNA expression, and mitochondrial respiration. However, it is unknown whether the IL-1β/IL-10 ratio based subgrouping is associated with changes in T cell cytokine profiles or monocyte cytokine profiles with non-TLR agonists. In ASD (n = 152) and non-ASD (n = 41) subjects, cytokine production by peripheral blood monocytes (PBMo) with TLR agonists and β-glucan, an inflammasome agonist, and T cell cytokine production by peripheral blood mononuclear cells (PBMCs) with recall antigens (Ags) (food and candida Ags) were concurrently measured. Changes in monocyte cytokine profiles were observed with β-glucan in the IL-1β/IL-10 ratio based ASD subgroups, along with changes in T cell cytokine production and ASD subgroup-specific correlations between T cell and monocyte cytokine production. Non-ASD controls revealed considerably less of such correlations. Altered innate immune responses in a subset of ASD children are not restricted to TLR pathways and correlated with changes in T cell cytokine production. Altered trained immunity may play a role in the above described changes. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Graphical abstract

26 pages, 3091 KiB

Open AccessArticle

ASD Phenotype—Genotype Associations in Concordant and Discordant Monozygotic and Dizygotic Twins Stratified by Severity of Autistic Traits

by Valerie W. Hu, Christine A. Devlin and Jessica J. Debski

Int. J. Mol. Sci. 2019, 20(15), 3804; https://doi.org/10.3390/ijms20153804 - 3 Aug 2019

Cited by 14 | Viewed by 5182

Abstract

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social communication coupled with stereotyped behaviors and restricted interests. Despite the high concordance rate for diagnosis, there is little information on the magnitude of genetic contributions to specific ASD behaviors. [...] Read more.

Autism spectrum disorder (ASD) is a highly heterogeneous neurodevelopmental disorder characterized by impaired social communication coupled with stereotyped behaviors and restricted interests. Despite the high concordance rate for diagnosis, there is little information on the magnitude of genetic contributions to specific ASD behaviors. Using behavioral/trait severity scores from the Autism Diagnostic Interview-Revised (ADI-R) diagnostic instrument, we compared the phenotypic profiles of mono- and dizygotic twins where both co-twins were diagnosed with ASD or only one twin had a diagnosis. The trait distribution profiles across the respective twin populations were first used for quantitative trait association analyses using publicly available genome-wide genotyping data. Trait-associated single nucleotide polymorphisms (SNPs) were then used for case-control association analyses, in which cases were defined as individuals in the lowest (Q1) and highest (Q4) quartiles of the severity distribution curves for each trait. While all of the ASD-diagnosed twins exhibited similar trait severity profiles, the non-autistic dizygotic twins exhibited significantly lower ADI-R item scores than the non-autistic monozygotic twins. Case-control association analyses of twins stratified by trait severity revealed statistically significant SNPs with odds ratios that clearly distinguished individuals in Q4 from those in Q1. While the level of shared genomic variation is a strong determinant of the severity of autistic traits in the discordant non-autistic twins, the similarity of trait profiles in the concordantly autistic dizygotic twins also suggests a role for environmental influences. Stratification of cases by trait severity resulted in the identification of statistically significant SNPs located near genes over-represented within autism gene datasets. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Graphical abstract

16 pages, 1391 KiB

Open AccessArticle

Network-Based Integrative Analysis of Genomics, Epigenomics and Transcriptomics in Autism Spectrum Disorders

by Noemi Di Nanni, Matteo Bersanelli, Francesca Anna Cupaioli, Luciano Milanesi, Alessandra Mezzelani and Ettore Mosca

Int. J. Mol. Sci. 2019, 20(13), 3363; https://doi.org/10.3390/ijms20133363 - 9 Jul 2019

Cited by 7 | Viewed by 5238

Abstract

Current studies suggest that autism spectrum disorders (ASDs) may be caused by many genetic factors. In fact, collectively considering multiple studies aimed at characterizing the basic pathophysiology of ASDs, a large number of genes has been proposed. Addressing the problem of molecular data [...] Read more.

Current studies suggest that autism spectrum disorders (ASDs) may be caused by many genetic factors. In fact, collectively considering multiple studies aimed at characterizing the basic pathophysiology of ASDs, a large number of genes has been proposed. Addressing the problem of molecular data interpretation using gene networks helps to explain genetic heterogeneity in terms of shared pathways. Besides, the integrative analysis of multiple omics has emerged as an approach to provide a more comprehensive view of a disease. In this work, we carry out a network-based meta-analysis of the genes reported as associated with ASDs by studies that involved genomics, epigenomics, and transcriptomics. Collectively, our analysis provides a prioritization of the large number of genes proposed to be associated with ASDs, based on genes’ relevance within the intracellular circuits, the strength of the supporting evidence of association with ASDs, and the number of different molecular alterations affecting genes. We discuss the presence of the prioritized genes in the SFARI (Simons Foundation Autism Research Initiative) database and in gene networks associated with ASDs by other investigations. Lastly, we provide the full results of our analyses to encourage further studies on common targets amenable to therapy. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Graphical abstract

31 pages, 3342 KiB

Open AccessArticle

High Functioning Autism with Missense Mutations in Synaptotagmin-Like Protein 4 (SYTL4) and Transmembrane Protein 187 (TMEM187) Genes: SYTL4- Protein Modeling, Protein-Protein Interaction, Expression Profiling and MicroRNA Studies

by Syed K. Rafi, Alberto Fernández-Jaén, Sara Álvarez, Owen W. Nadeau and Merlin G. Butler

Int. J. Mol. Sci. 2019, 20(13), 3358; https://doi.org/10.3390/ijms20133358 - 9 Jul 2019

Cited by 14 | Viewed by 5687

Abstract

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1; c.835C>T; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28; c.708G>T; p. [...] Read more.

We describe a 7-year-old male with high functioning autism spectrum disorder (ASD) and maternally-inherited rare missense variant of Synaptotagmin-like protein 4 (SYTL4) gene (Xq22.1; c.835C>T; p.Arg279Cys) and an unknown missense variant of Transmembrane protein 187 (TMEM187) gene (Xq28; c.708G>T; p. Gln236His). Multiple in-silico predictions described in our study indicate a potentially damaging status for both X-linked genes. Analysis of predicted atomic threading models of the mutant and the native SYTL4 proteins suggest a potential structural change induced by the R279C variant which eliminates the stabilizing Arg279-Asp60 salt bridge in the N-terminal half of the SYTL4, affecting the functionality of the protein’s critical RAB-Binding Domain. In the European (Non-Finnish) population, the allele frequency for this variant is 0.00042. The SYTL4 gene is known to directly interact with several members of the RAB family of genes, such as, RAB27A, RAB27B, RAB8A, and RAB3A which are known autism spectrum disorder genes. The SYTL4 gene also directly interacts with three known autism genes: STX1A, SNAP25 and STXBP1. Through a literature-based analytical approach, we identified three of five (60%) autism-associated serum microRNAs (miRs) with high predictive power among the total of 298 mouse Sytl4 associated/predicted microRNA interactions. Five of 13 (38%) miRs were differentially expressed in serum from ASD individuals which were predicted to interact with the mouse equivalent Sytl4 gene. TMEM187 gene, like SYTL4, is a protein-coding gene that belongs to a group of genes which host microRNA genes in their introns or exons. The novel Q236H amino acid variant in the TMEM187 in our patient is near the terminal end region of the protein which is represented by multiple sequence alignments and hidden Markov models, preventing comparative structural analysis of the variant harboring region. Like SYTL4, the TMEM187 gene is expressed in the brain and interacts with four known ASD genes, namely, HCFC1; TMLHE; MECP2; and GPHN. TMM187 is in linkage with MECP2, which is a well-known determinant of brain structure and size and is a well-known autism gene. Other members of the TMEM gene family, TMEM132E and TMEM132D genes are associated with bipolar and panic disorders, respectively, while TMEM231 is a known syndromic autism gene. Together, TMEM187 and SYTL4 genes directly interact with recognized important ASD genes, and their mRNAs are found in extracellular vesicles in the nervous system and stimulate target cells to translate into active protein. Our evidence shows that both these genes should be considered as candidate genes for autism. Additional biological testing is warranted to further determine the pathogenicity of these gene variants in the causation of autism. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

15 pages, 4493 KiB

Open AccessArticle

Altered Intestinal Morphology and Microbiota Composition in the Autism Spectrum Disorders Associated SHANK3 Mouse Model

by Ann Katrin Sauer, Juergen Bockmann, Konrad Steinestel, Tobias M. Boeckers and Andreas M. Grabrucker

Int. J. Mol. Sci. 2019, 20(9), 2134; https://doi.org/10.3390/ijms20092134 - 30 Apr 2019

Cited by 54 | Viewed by 8376

Abstract

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin [...] Read more.

Autism spectrum disorders (ASD) are a group of neurodevelopmental disorders characterized by deficits in social interaction and communication, and repetitive behaviors. In addition, co-morbidities such as gastro-intestinal problems have frequently been reported. Mutations and deletion of proteins of the SH3 and multiple ankyrin repeat domains (SHANK) gene-family were identified in patients with ASD, and Shank knock-out mouse models display autism-like phenotypes. SHANK3 proteins are not only expressed in the central nervous system (CNS). Here, we show expression in gastrointestinal (GI) epithelium and report a significantly different GI morphology in Shank3 knock-out (KO) mice. Further, we detected a significantly altered microbiota composition measured in feces of Shank3 KO mice that may contribute to inflammatory responses affecting brain development. In line with this, we found higher E. coli lipopolysaccharide levels in liver samples of Shank3 KO mice, and detected an increase in Interleukin-6 and activated astrocytes in Shank3 KO mice. We conclude that apart from its well-known role in the CNS, SHANK3 plays a specific role in the GI tract that may contribute to the ASD phenotype by extracerebral mechanisms. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Graphical abstract

14 pages, 255 KiB

Open AccessArticle

Parent-of-Origin Effects in 15q11.2 BP1-BP2 Microdeletion (Burnside-Butler) Syndrome

by Kyle W. Davis, Moises Serrano, Sara Loddo, Catherine Robinson, Viola Alesi, Bruno Dallapiccola, Antonio Novelli and Merlin G. Butler

Int. J. Mol. Sci. 2019, 20(6), 1459; https://doi.org/10.3390/ijms20061459 - 22 Mar 2019

Cited by 25 | Viewed by 4928

Abstract

To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER [...] Read more.

To identify whether parent-of-origin effects (POE) of the 15q11.2 BP1-BP2 microdeletion are associated with differences in clinical features in individuals inheriting the deletion, we collected 71 individuals reported with phenotypic data and known inheritance from a clinical cohort, a research cohort, the DECIPHER database, and the primary literature. Chi-squared and Mann-Whitney U tests were used to test for differences in specific and grouped clinical symptoms based on parental inheritance and proband gender. Analyses controlled for sibling sets and individuals with additional variants of uncertain significance (VOUS). Among all probands, maternal deletions were associated with macrocephaly (p = 0.016) and autism spectrum disorder (ASD; p = 0.02), while paternal deletions were associated with congenital heart disease (CHD; p = 0.004). Excluding sibling sets, maternal deletions were associated with epilepsy as well as macrocephaly (p < 0.05), while paternal deletions were associated with CHD and abnormal muscular phenotypes (p < 0.05). Excluding sibling sets and probands with an additional VOUS, maternal deletions were associated with epilepsy (p = 0.019) and paternal deletions associated with muscular phenotypes (p = 0.008). Significant gender-based differences were also observed. Our results supported POEs of this deletion and included macrocephaly, epilepsy and ASD in maternal deletions with CHD and abnormal muscular phenotypes seen in paternal deletions. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

14 pages, 1374 KiB

Open AccessArticle

GeneAnalytics Pathways and Profiling of Shared Autism and Cancer Genes

by Alexander P. Gabrielli, Ann M. Manzardo and Merlin G. Butler

Int. J. Mol. Sci. 2019, 20(5), 1166; https://doi.org/10.3390/ijms20051166 - 7 Mar 2019

Cited by 19 | Viewed by 4847

Abstract

Recent research revealed that autism spectrum disorders (ASD) and cancer may share common genetic architecture, with evidence first reported with the PTEN gene. There are approximately 800 autism genes and 3500 genes associated with cancer. The VarElect phenotype program was chosen to identify [...] Read more.

Recent research revealed that autism spectrum disorders (ASD) and cancer may share common genetic architecture, with evidence first reported with the PTEN gene. There are approximately 800 autism genes and 3500 genes associated with cancer. The VarElect phenotype program was chosen to identify genes jointly associated with both conditions based on genomic information stored in GeneCards. In total, 138 overlapping genes were then profiled with GeneAnalytics, an analysis pathway enrichment tool utilizing existing gene datasets to identify shared pathways, mechanisms, and phenotypes. Profiling the shared gene data identified seven significantly associated diseases of 2310 matched disease entities with factors implicated in shared pathology of ASD and cancer. These included 371 super-pathways of 455 matched entities reflecting major cell-signaling pathways and metabolic disturbances (e.g., CREB, AKT, GPCR); 153 gene ontology (GO) biological processes of 226 matched processes; 41 GO molecular functions of 78 matched functions; and 145 phenotypes of 232 matched phenotypes. The entries were scored and ranked using a matching algorithm that takes into consideration genomic expression, sequencing, and microarray datasets with cell or tissue specificity. Shared mechanisms may lead to the identification of a common pathology and a better understanding of causation with potential treatment options to lessen the severity of ASD-related symptoms in those affected. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

Review

Jump to: Research, Other

29 pages, 626 KiB

Open AccessReview

Risk Factors for Unhealthy Weight Gain and Obesity among Children with Autism Spectrum Disorder

by Khushmol K. Dhaliwal, Camila E. Orsso, Caroline Richard, Andrea M. Haqq and Lonnie Zwaigenbaum

Int. J. Mol. Sci. 2019, 20(13), 3285; https://doi.org/10.3390/ijms20133285 - 4 Jul 2019

Cited by 74 | Viewed by 16508

Abstract

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by social and communication deficits and repetitive behaviors. Children with ASD are also at a higher risk for developing overweight or obesity than children with typical development (TD). Childhood obesity has been associated with [...] Read more.

Autism Spectrum Disorder (ASD) is a developmental disorder characterized by social and communication deficits and repetitive behaviors. Children with ASD are also at a higher risk for developing overweight or obesity than children with typical development (TD). Childhood obesity has been associated with adverse health outcomes, including insulin resistance, diabetes, heart disease, and certain cancers. Importantly some key factors that play a mediating role in these higher rates of obesity include lifestyle factors and biological influences, as well as secondary comorbidities and medications. This review summarizes current knowledge about behavioral and lifestyle factors that could contribute to unhealthy weight gain in children with ASD, as well as the current state of knowledge of emerging risk factors such as the possible influence of sleep problems, the gut microbiome, endocrine influences and maternal metabolic disorders. We also discuss some of the clinical implications of these risk factors and areas for future research. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

10 pages, 1079 KiB

Open AccessReview

IQSEC2-Associated Intellectual Disability and Autism

by Nina S. Levy, George K. E. Umanah, Eli J. Rogers, Reem Jada, Orit Lache and Andrew P. Levy

Int. J. Mol. Sci. 2019, 20(12), 3038; https://doi.org/10.3390/ijms20123038 - 21 Jun 2019

Cited by 26 | Viewed by 5604

Abstract

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. [...] Read more.

Mutations in IQSEC2 cause intellectual disability (ID), which is often accompanied by seizures and autism. A number of studies have shown that IQSEC2 is an abundant protein in excitatory synapses and plays an important role in neuronal development as well as synaptic plasticity. Here, we review neuronal IQSEC2 signaling with emphasis on those aspects likely to be involved in autism. IQSEC2 is normally bound to N-methyl-D-aspartate (NMDA)-type glutamate receptors via post synaptic density protein 95 (PSD-95). Activation of NMDA receptors results in calcium ion influx and binding to calmodulin present on the IQSEC2 IQ domain. Calcium/calmodulin induces a conformational change in IQSEC2 leading to activation of the SEC7 catalytic domain. GTP is exchanged for GDP on ADP ribosylation factor 6 (ARF6). Activated ARF6 promotes downregulation of surface α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-type glutamate receptors through a c-jun N terminal kinase (JNK)-mediated pathway. NMDA receptors, AMPA receptors, and PSD-95 are all known to be adversely affected in autism. An IQSEC2 transgenic mouse carrying a constitutively active mutation (A350V) shows autistic features and reduced levels of surface AMPA receptor subunit GluA2. Sec7 activity and AMPA receptor recycling are presented as two targets, which may respond to drug treatment in IQSEC2-associated ID and autism. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

15 pages, 872 KiB

Open AccessReview

Crmp4-KO Mice as an Animal Model for Investigating Certain Phenotypes of Autism Spectrum Disorders

by Ritsuko Ohtani-Kaneko

Int. J. Mol. Sci. 2019, 20(10), 2485; https://doi.org/10.3390/ijms20102485 - 20 May 2019

Cited by 8 | Viewed by 4624

Abstract

Previous research has demonstrated that the collapsin response mediator protein (CRMP) family is involved in the formation of neural networks. A recent whole-exome sequencing study identified a de novo variant (S541Y) of collapsin response mediator protein 4 (CRMP4) in a male patient with [...] Read more.

Previous research has demonstrated that the collapsin response mediator protein (CRMP) family is involved in the formation of neural networks. A recent whole-exome sequencing study identified a de novo variant (S541Y) of collapsin response mediator protein 4 (CRMP4) in a male patient with autism spectrum disorder (ASD). In addition, Crmp4-knockout (KO) mice show some phenotypes similar to those observed in human patients with ASD. For example, compared with wild-type mice, Crmp4-KO mice exhibit impaired social interaction, abnormal sensory sensitivities, broader distribution of activated (c-Fos expressing) neurons, altered dendritic formation, and aberrant patterns of neural gene expressions, most of which have sex differences. This review summarizes current knowledge regarding the role of CRMP4 during brain development and discusses the possible contribution of CRMP4 deficiencies or abnormalities to the pathogenesis of ASD. Crmp4-KO mice represent an appropriate animal model for investigating the mechanisms underlying some ASD phenotypes, such as impaired social behavior, abnormal sensory sensitivities, and sex-based differences, and other neurodevelopmental disorders associated with sensory processing disorders. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Graphical abstract

Other

Jump to: Research, Review

16 pages, 2664 KiB

Open AccessCase Report

Significantly Elevated FMR1 mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing

by Michael Field, Tracy Dudding-Byth, Marta Arpone, Emma K. Baker, Solange M. Aliaga, Carolyn Rogers, Chriselle Hickerton, David Francis, Dean G. Phelan, Elizabeth E. Palmer, David J. Amor, Howard Slater, Lesley Bretherton, Ling Ling and David E. Godler

Int. J. Mol. Sci. 2019, 20(16), 3907; https://doi.org/10.3390/ijms20163907 - 11 Aug 2019

Cited by 14 | Viewed by 5308

Abstract

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This [...] Read more.

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with ≥200 cytosine-guanine-guanine (CGG) repeats, and a decrease in FMR1 mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55–199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had FMR1 mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

7 pages, 604 KiB

Open AccessCommentary

Magnesium Supplement and the 15q11.2 BP1–BP2 Microdeletion (Burnside–Butler) Syndrome: A Potential Treatment?

by Merlin G. Butler

Int. J. Mol. Sci. 2019, 20(12), 2914; https://doi.org/10.3390/ijms20122914 - 14 Jun 2019

Cited by 19 | Viewed by 10409

Abstract

The 15q11.2 BP1–BP2 microdeletion (Burnside–Butler) syndrome is an emerging disorder that encompasses four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5). When disturbed, these four genes can lead to cognitive impairment, language and/or motor delay, psychiatric/behavioral problems (attention-deficit hyperactivity, autism, dyslexia, schizophrenia/paranoid [...] Read more.

The 15q11.2 BP1–BP2 microdeletion (Burnside–Butler) syndrome is an emerging disorder that encompasses four genes (NIPA1, NIPA2, CYFIP1, and TUBGCP5). When disturbed, these four genes can lead to cognitive impairment, language and/or motor delay, psychiatric/behavioral problems (attention-deficit hyperactivity, autism, dyslexia, schizophrenia/paranoid psychosis), ataxia, seizures, poor coordination, congenital anomalies, and abnormal brain imaging. This microdeletion was reported as the most common cytogenetic finding when using ultra-high- resolution chromosomal microarrays in patients presenting for genetic services due to autism with or without additional clinical features. Additionally, those individuals with Prader–Willi or Angelman syndromes having the larger typical 15q11–q13 type I deletion which includes the 15q11.2 BP1–BP2 region containing the four genes, show higher clinical severity than those having the smaller 15q11–q13 deletion where these four genes are intact. Two of the four genes (i.e., NIPA1 and NIPA2) are expressed in the brain and encode magnesium transporters. Magnesium is required in over 300 enzyme systems that are critical for multiple cellular functions, energy expenditure, protein synthesis, DNA transcription, and muscle and nerve function. Low levels of magnesium are found in those with seizures, depression, and acute or chronic brain diseases. Anecdotally, parents have administered magnesium supplements to their children with the 15q11.2 BP1–BP2 microdeletion and have observed improvement in behavior and clinical presentation. These observations require more attention from the medical community and should include controlled studies to determine if magnesium supplements could be a treatment option for this microdeletion syndrome and also for a subset of individuals with Prader–Willi and Angelman syndromes. Full article

(This article belongs to the Special Issue Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019)

► Show Figures

Figure 1

Journal Menu

Journal Browser

Identification and Characterization of Genetic Components in Autism Spectrum Disorders 2019

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Related Special Issues

Published Papers (13 papers)

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI