Non-syndromic Autosomal Recessive Intellectual Disability Research Articles

The CB1 receptor interacts with cereblon and drives cereblon deficiency-associated memory shortfalls.

Cereblon/CRBN is a substrate-recognition component of the Cullin4A-DDB1-Roc1 E3 ubiquitin ligase complex. Destabilizing mutations in the human CRBN gene cause a form of autosomal recessive non-syndromic intellectual disability (ARNSID) that is modelled by knocking-out the mouse Crbn gene. A reduction in excitatory neurotransmission has been proposed as an underlying mechanism of the disease. However, the precise factors eliciting this impairment remain mostly unknown. Here we report that CRBN molecules selectively located on glutamatergic neurons are necessary for proper memory function. Combining various in vivo approaches, we show that the cannabinoid CB1 receptor (CB1R), a key suppressor of synaptic transmission, is overactivated in CRBN deficiency-linked ARNSID mouse models, and that the memory deficits observed in these animals can be rescued by acute CB1R-selective pharmacological antagonism. Molecular studies demonstrated that CRBN interacts physically with CB1R and impairs the CB1R-Gi/o-cAMP-PKA pathway in a ubiquitin ligase-independent manner. Taken together, these findings unveil that CB1R overactivation is a driving mechanism of CRBN deficiency-linked ARNSID and anticipate that the antagonism of CB1R could constitute a new therapy for this orphan disease.

Emerging Epidemiological Data on Rare Intellectual Disability Syndromes from Analyzing the Data of a Large Iranian Cohort.

Intellectual disability (ID) is a genetically heterogeneous condition, and so far, 1679 human genes have been identified for this phenotype. Countries with a high rate of parental consanguinity, such as Iran, provide an excellent opportunity to identify the remaining novel ID genes, especially those with an autosomal recessive (AR) mode of inheritance. This study aimed to investigate the most prevalent ID genes identified via next-generation sequencing (NGS) in a large ID cohort at the Genetics Research Center (GRC) of the University of Social Welfare and Rehabilitation Sciences. First, we surveyed the epidemiological data of 619 of 1295 families in our ID cohort, who referred to the Genetics Research Center from all over the country between 2004 and 2021 for genetic investigation via the NGS pipeline. We then compared our data with those of several prominent studies conducted in consanguineous countries. Data analysis, including cohort data extraction, categorization, and comparison, was performed using the R program version 4.1.2. We categorized the most common ID genes that were mutated in more than two families into 17 categories. The most common syndromic ID in our cohort was AP4 deficiency syndrome, and the most common non-syndromic autosomal recessive intellectual disability (ARID) gene was ASPM. We identified two unrelated families for the 36 ID genes. We found 14 genes in common between our cohort and the Arab and Pakistani groups, of which three genes (AP4M1, AP4S1, and ADGRG1) were repeated more than once. To date, there has been no comprehensive targeted NGS platform for the detection of ID genes in our country. Due to the large sample size of our study, our data may provide the initial step toward designing an indigenously targeted NGS platform for the diagnosis of ID, especially common ARID in our population.

Non-syndromic Intellectual Disability: An Experimental In-Depth Exploration of Inheritance Pattern, Phenotypic Presentation, and Genomic Composition.

Background Intellectual disability (ID), also termed mental retardation (MR), is a neurodevelopmental disorder characterized by an intelligence quotient (IQ) of 70 or below and a deficit in at least two behaviors associated with adaptive functioning. The condition is further classified into syndromic intellectual disability (S-ID) and non-syndromic intellectual disability (NS-ID). This study highlights the genes associated with NS-ID. Objectives A genetic study was performed on two Pakistani families to know the inheritance patterns, clinical phenotypes, and molecular genetics of affected individuals with NS-ID. Methodology Samples were collected from two families: families A and B. All affected individuals in both families were diagnosed by a neurologist. Written informed consent was taken from the affected individuals and guardians before collecting the data and sample. Family A belongs to the Swabi District of Pakistan having four affected individuals, out of whom three were male and one was female. Family B also belongs to the Swabi District of Pakistan having two affected individuals, out of whom one was male and one was female. A total of 10 candidate genes were selected and were further screened by microarray analysis. Results In family A, this analysis identified a region of 9.6 Mb on chromosome 17q11.2-q12 between the single nucleotide polymorphisms (SNPs) rs953527 and rs2680398. The region was genotyped using microsatellite markers to confirm the haplotypes in all family members. Based on the phenotype-genotype relationship, 10 possible candidate genes were selected out of more than 140 genes in this critical region of 9.6 Mb. In family B, homozygosity mapping through microarray identified four homozygous areas of affected individuals: two (27,324,822-59,122,062 and 96,423,252123,656,241) on chromosome 8, one (14,785,224-19,722,760) on chromosome 9, and one (126173647-126215644) on chromosome 11. Conclusion An autosomal recessive pattern was found in the pedigrees of both families A and B. Phenotypically affected individuals showed IQ levels below 70. Three genes, CDK5R1, OMG, and EV12A, were found on chromosome 17q11.2-q12 region of affected individuals in family A with high expression in the frontal cortex of the brain, hippocampus, and spinal cord, respectively. Other regions on chromosomes 8, 9, and 11 as evident from the affected individuals in family B can also contribute to the non-syndromic autosomal recessive intellectual disability (NS-ARID). Further research is needed to find the association of these genes with intelligence and other neuropsychiatric conditions.

Defective neurite elongation and branching in Nibp/Trappc9 deficient zebrafish and mice.

Loss of function in transport protein particles (TRAPP) links a new set of emerging genetic disorders called "TRAPPopathies". One such disorder is NIBP syndrome, characterized by microcephaly and intellectual disability, and caused by mutations of NIBP/TRAPPC9, a crucial and unique member of TRAPPII. To investigate the neural cellular/molecular mechanisms underlying microcephaly, we developed Nibp/Trappc9-deficient animal models using different techniques, including morpholino knockdown and CRISPR/Cas mutation in zebrafish and Cre/LoxP-mediated gene targeting in mice. Nibp/Trappc9 deficiency impaired the stability of the TRAPPII complex at actin filaments and microtubules of neurites and growth cones. This deficiency also impaired elongation and branching of neuronal dendrites and axons, without significant effects on neurite initiation or neural cell number/types in embryonic and adult brains. The positive correlation of TRAPPII stability and neurite elongation/branching suggests a potential role for TRAPPII in regulating neurite morphology. These results provide novel genetic/molecular evidence to define patients with a type of non-syndromic autosomal recessive intellectual disability and highlight the importance of developing therapeutic approaches targeting the TRAPPII complex to cure TRAPPopathies.

A novel homozygous mutation in TRAPPC9 gene causing autosomal recessive non-syndromic intellectual disability

BackgroundThe etiology of intellectual disabilities is diverse and includes both genetic and environmental factors. The genetic causes of intellectual disabilities range from chromosomal aberrations to single gene disorders. The TRAPPC9 gene has been reported to cause autosomal recessive forms of intellectual disabilities in 56 patients from consanguineous and non-consanguineous families around the world.MethodsWe analyzed two siblings with intellectual disability, microcephaly and delayed motor and speech development from a consanguineous Sudanese family. Genomic DNA was screened for mutations using NGS panel (NextSeq500 Illumina) testing 173 microcephaly associated genes in the Molecular Genetics service in Robert Debre hospital in Paris, France.ResultsA novel homozygous mutation (NM_031466.7 (TRAPPC9):c.2288dup, p. (Val764Glyfs*7) in exon 14 of TRAPPC9 gene was found in the two patients. The mutation was predicted to cause nonsense mediated decay (NSMD) using SIFT prediction tool. The variant has not been found in either gnomAD or Exac databases. Both parents were heterozygous (carriers) to the mutation.ConclusionThis is the first study to report patients with TRAPPC9-related disorder from Sub-Saharan Africa.

A Missense Mutation in the HMNT Gene Responsible for Autosomal Recessive Intellectual Disability in an Iranian Family with Consanguineous Marriage

Background and Aims: One of the neurotransmitters in the brain is Histamine which acts as several biological mechanism regulators like inflammation, gastric acid secretion, and neuromodulation. Inactivation of Histamine occurs by histamine N-methyltransferase (HNMT) enzyme. The HNMT transfers a methyl group from S-adenosyl-L-methionine to Histamine and is the main process for the termination of neurotransmission actions of Histamine in the mammalian central nervous system.
 Materials and Methods: In this case, a family was referred to the genetic clinic to diagnose the cause of their disorder. The clinical form, pedigree, and questionnaire were completed for the family, and the parents gave their written consent for all tests and photographs publication. Both siblings have moderate learning and intellectual disability. Whole exome sequencing was performed and Sanger sequencing for co-segregation was used.
 Results: Bioinformatics analysis revealed a homozygous missense variant in HNMT (c.623T>C p.Leu208Pro) which causes non-syndromic autosomal recessive intellectual disability in this consanguineous family. Analysis of segregation confirmed this mutation. P.Leu208Pro mutation reduces the stability of the protein, which reduces the inactivation of Histamine.
 Conclusion: HNMT should be considered an important gene in the genetic evaluation of consanguineous families with intellectual disability.

Prevalence of Epilepsy with Autosomal Recessive Intellectual Disability in Consanguineous Families

Background: Intellectual disability (I.D) is the limitation of cognitive impairment and decreased ability of learning of a person. It is a type of neurological genetic disease, which results in incomplete or retarded/ arrested development of the brain. I.D is one of the most common health problem worldwide. These patients have decreased intellectual functions and at least limitation in their two adoptive skills such as writing or reading abilities, communication ability and self-care etc. While epilepsy is a neurodevelopment disease presented as abrupt & episodic recurrence of sensory disturbance, loss of consciousness or convulsions, related with the abnormality of electrical activities in the brain. Epilepsy is an illness of CNS that result in abnormal brain activity, causing periods of unusual behavior or seizures, loss of awareness, and sometimes sensations. Methods: This study was done from April 2014 to February 2016. The inclusion criteria for these patients were consanguineous families with two or more than two effected persons. All the I.D patients and their families were interviewed one by one. Blood samples were collected under hygienic method. Each patient were examined thoroughly and noted the points with the help of different proformas. Collected blood collection were stored in laboratory. After DNA extraction ,PCR was done. After extraction exome sequencing process used to find the pathogenic /effected variants. CATCH used for the analyzed of data. Sanger Sequencing was applied to note the segregation. Results: In ID-family1 the variant of AP4B1 was segregated with the disease phenotype. Mutation in AP4B1 is known to cause intellectual disability. In ID-family2 the variants of WDR62, EML2 and KCNK6 were co-segregated with diseased phenotype. But only changes in WDR62 which is known as a cause of intellectual disability. These patients also have symptoms of epilepsy. In ID-family3 exome sequencing data reveal no putative variants. Conclusion: This study was done in three consanguineous families to determine the responsible mutant genes for the disorder of intellectual disability. Their Exome sequencing showed putative mutations in AP4B1 and WDR62 in two out of three families. In third family we could not locate any putative mutation. Keywords: Epilepsy, Intellectual disability, Autosomal recessive disorders, Autosomal recessive nonsyndromic intellectual disability, Seizures, Neurological, Behavioral Abnormality, Central Nervous System, Electroencephalogram.

Co-segregation of variant NSUN2 Lue198Arg among Iranian family with intellectual disability: a case report

BackgroundIntellectual disability is characterized by impairments in adaptive behavior and cognitive functioning manifested during the developmental period. Since disabilities are heterogeneous, variant analysis can help us confirm and accurately diagnose children with intellectual disabilities. Some papers reported that bi-allelic variants of the NSUN2 gene caused a group of neurological disorders, including non-syndromic autosomal recessive intellectual disability (NS-ARID), Dubowitz syndrome, and familial restrictive cardiomyopathy 1 (RCM1). We report on a consanguineous family with three siblings diagnosed with intellectual disability.Case presentationThe 7-year-old female was referred to Ali-Asghar hospital, Zahedan, Iran, with clinical manifestations comprising moderate intellectual disability, ptosis, long face, and short stature. Chromosome banding, metabolic testing, and magnetic resonance imaging examinations revealed no abnormalities. Accordingly, other affected siblings born of the same parents were considered. Whole-exome sequencing (WES) was conducted on the sufferer to consider NS-ARID variants. Findings identified a variant with uncertain significance (NM_017755.6: c.593 T > G) in the NSUN2 gene in the proband. This variant was confirmed through Sanger sequencing of the affected and unaffected family members. Besides, the computational results showed that the L198R exchange could change the interaction between wild-type and other residues in the protein. The affected patients with NS-ARID had similar clinical characteristics and genetic abnormalities.ConclusionTaken together, we described the variant in three Iranian siblings; further expanding of the other variants involved in the disease will be evident by using high-throughput sequencing technologies.

Haploinsufficiency of the Attention-Deficit/Hyperactivity Disorder Risk Gene St3gal3 in Mice Causes Alterations in Cognition and Expression of Genes Involved in Myelination and Sialylation.

Genome wide association meta-analysis identified ST3GAL3, a gene encoding the beta-galactosidase-alpha-2,3-sialyltransferase-III, as a risk gene for attention-deficit/hyperactivity disorder (ADHD). Although loss-of-function mutations in ST3GAL3 are implicated in non-syndromic autosomal recessive intellectual disability (NSARID) and West syndrome, the impact of ST3GAL3 haploinsufficiency on brain function and the pathophysiology of neurodevelopmental disorders (NDDs), such as ADHD, is unknown. Since St3gal3 null mutant mice display severe developmental delay and neurological deficits, we investigated the effects of partial inactivation of St3gal3 in heterozygous (HET) knockout (St3gal3±) mice on behavior as well as expression of markers linked to myelination processes and sialylation pathways. Our results reveal that male St3gal3 HET mice display cognitive deficits, while female HET animals show increased activity, as well as increased cognitive control, compared to their wildtype littermates. In addition, we observed subtle alterations in the expression of several markers implicated in oligodendrogenesis, myelin formation, and protein sialylation as well as cell adhesion/synaptic target glycoproteins of ST3GAL3 in a brain region- and/or sex-specific manner. Taken together, our findings indicate that haploinsufficiency of ST3GAL3 results in a sex-dependent alteration of cognition, behavior and markers of brain plasticity.

A Novel LINS1 Truncating Mutation in Autosomal Recessive Nonsyndromic Intellectual Disability.

The large majority of cases with intellectual disability are syndromic (i.e. occur with other well-defined clinical phenotypes) and have been studied extensively. Autosomal recessive nonsyndromic intellectual disability is a group of genetically heterogeneous disorders for which a number of potentially causative genes have been identified although the molecular basis of most of them remains unexplored. Here, we report the clinical characteristics and genetic findings of a family with two male siblings affected with autosomal recessive nonsyndromic intellectual disability. Whole exome sequencing was carried out on two affected male siblings and unaffected parents. A potentially pathogenic variant identified in this study was confirmed by Sanger sequencing to be inherited in an autosomal recessive fashion. We identified a novel nonsense mutation (p.Gln368Ter) in the LINS1 gene which leads to loss of 389 amino acids in the C-terminus of the encoded protein. The truncation mutation causes a complete loss of LINES_C domain along with loss of three known phosphorylation sites and a known ubiquitylation site in addition to other evolutionarily conserved regions of LINS1. LINS1 has been reported to cause MRT27 (mental retardation, autosomal recessive 27), a rare autosomal recessive nonsyndromic intellectual disability, with limited characterization of the phenotype. Identification of a potentially pathogenic truncating mutation in LINS1 in two profoundly intellectually impaired patients also confirms its role in cognition.

Conditional Deletion of CC2D1A Reduces Hippocampal Synaptic Plasticity and Impairs Cognitive Function through Rac1 Hyperactivation.

Coiled-coil and C2 domain containing 1A (CC2D1A) is an evolutionarily conserved protein, originally identified as a nuclear factor-κB activator through a large-scale screen of human genes. Mutations in the human Cc2d1a gene result in autosomal recessive nonsyndromic intellectual disability. It remains unclear, however, how Cc2d1a mutation leads to alterations in brain function. Here, we have taken advantage of Cre/loxP recombinase-based strategy to conditionally delete Cc2d1a exclusively from excitatory neurons of male mouse forebrain to examine its role in hippocampal synaptic plasticity and cognitive function. We confirmed the expression of CC2D1A protein and mRNA in the mouse hippocampus. Double immunofluorescence staining showed that CC2D1A is expressed in both excitatory and inhibitory neurons of the adult hippocampus. Conditional deletion of Cc2d1a (cKO) from excitatory neurons leads to impaired performance in object location memory test and altered anxiety-like behavior. Consistently, cKO mice displayed a deficit in the maintenance of LTP in the CA1 region of hippocampal slices. Cc2d1a deletion also resulted in decreased complexity of apical and basal dendritic arbors of CA1 pyramidal neurons. An enhanced basal Rac1 activity was observed following Cc2d1a deletion, and this enhancement was mediated by reduced SUMO-specific protease 1 (SENP1) and SENP3 expression, thus increasing the amount of Rac1 SUMOylation. Furthermore, partial blockade of Rac1 activity rescued impairments in LTP and object location memory performance in cKO mice. Together, our results implicate Rac1 hyperactivity in synaptic plasticity and cognitive deficits observed in Cc2d1a cKO mice and reveal a novel role for CC2D1A in regulating hippocampal synaptic function.SIGNIFICANCE STATEMENT CC2D1A is abundantly expressed in the brain, but there is little known about its physiological function. Taking advantage of Cc2d1a cKO mice, the present study highlights the importance of CC2D1A in the maintenance of LTP at Schaffer collateral-CA1 synapses and the formation of hippocampus-dependent long-term object location memory. Our findings establish a critical link between elevated Rac1 activity, structural and synaptic plasticity alterations, and cognitive impairment caused by Cc2d1a deletion. Moreover, partial blockade of Rac1 activity rescues synaptic plasticity and memory deficits in Cc2d1a cKO mice. Such insights may have implications for the utility of Rac1 inhibitors in the treatment of intellectual disability caused by Cc2d1a mutations in human patients.

B3GALNT2 mutations associated with non-syndromic autosomal recessive intellectual disability reveal a lack of genotype\u2013phenotype associations in the muscular dystrophy-dystroglycanopathies

BackgroundThe phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients.MethodsUsing linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2.ResultsThe first family comprises two brothers of Dutch non-consanguineous parents presenting with mild ID and behavioral problems. Immunohistochemical analysis of muscle biopsy revealed no significant aberrations, in line with the absence of a muscular phenotype in the affected siblings. The second family includes five affected individuals from an Iranian consanguineous kindred with mild-to-moderate intellectual disability (ID) and epilepsy without any notable neuroimaging, muscle, or eye abnormalities. Complementation assays of the compound heterozygous mutations identified in the two brothers had a comparable effect on the O-glycosylation of α-dystroglycan as previously reported mutations that are associated with severe muscular phenotypes.ConclusionsIn conclusion, we show that mutations in B3GALNT2 can give rise to a novel MDDG syndrome presentation, characterized by ID associated variably with seizure, but without any apparent muscular involvement. Importantly, B3GALNT2 activity does not fully correlate with the severity of the phenotype as assessed by the complementation assay.

Identification of a novel homozygous TRAPPC9 gene mutation causing non‐syndromic intellectual disability, speech disorder, and secondary microcephaly

TRAPPC9 gene mutations have been linked recently to autosomal recessive mental retardation 13 (MRT13; MIM#613192) with only eight families reported world-wide. We assessed patients from two consanguineous pedigrees of Pakistani descent with non-syndromic intellectual disability and postnatal microcephaly through whole exome sequencing (WES) and cosegregation analysis. Here we report six further patients from two pedigrees with homozygous TRAPPC9 gene mutations, the novel nonsense mutation c.2065G>T (p.E689*) and the previously identified nonsense mutation c.1423C>T (p.R475*). We provide an overview of previously reported clinical features and highlight common symptoms and variability of MRT13. Common findings are intellectual disability and absent speech, and frequently microcephaly, motor delay and pathological findings on MRI including diminished cerebral white matter volume are present. Mutations in TRAPPC9 should be considered in non-syndromic autosomal recessive intellectual disability with severe speech disorder.

Ohgata, the Single Drosophila Ortholog of Human Cereblon, Regulates Insulin Signaling-dependent Organismic Growth

Cereblon (CRBN) is a substrate receptor of the E3 ubiquitin ligase complex that is highly conserved in animals and plants. CRBN proteins have been implicated in various biological processes such as development, metabolism, learning, and memory formation, and their impairment has been linked to autosomal recessive non-syndromic intellectual disability and cancer. Furthermore, human CRBN was identified as the primary target of thalidomide teratogenicity. Data on functional analysis of CRBN family members in vivo, however, are still scarce. Here we identify Ohgata (OHGT), the Drosophila ortholog of CRBN, as a regulator of insulin signaling-mediated growth. Using ohgt mutants that we generated by targeted mutagenesis, we show that its loss results in increased body weight and organ size without changes of the body proportions. We demonstrate that ohgt knockdown in the fat body, an organ analogous to mammalian liver and adipose tissue, phenocopies the growth phenotypes. We further show that overgrowth is due to an elevation of insulin signaling in ohgt mutants and to the down-regulation of inhibitory cofactors of circulating Drosophila insulin-like peptides (DILPs), named acid-labile subunit and imaginal morphogenesis protein-late 2. The two inhibitory proteins were previously shown to be components of a heterotrimeric complex with growth-promoting DILP2 and DILP5. Our study reveals OHGT as a novel regulator of insulin-dependent organismic growth in Drosophila.

Nuclear cereblon modulates transcriptional activity of Ikaros and regulates its downstream target, enkephalin, in human neuroblastoma cells

The gene coding cereblon (CRBN) was originally identified in genetic linkage analysis of mild autosomal recessive nonsyndromic intellectual disability. CRBN has broad localization in both the cytoplasm and nucleus. However, the significance of nuclear CRBN remains unknown. In the present study, we aimed to elucidate the role of CRBN in the nucleus. First, we generated a series of CRBN deletion mutants and determined the regions responsible for the nuclear localization. Only CRBN protein lacking the N-terminal region was localized outside of the nucleus, suggesting that the N-terminal region is important for its nuclear localization. CRBN was also identified as a thalidomide-binding protein and component of the cullin-4-containing E3 ubiquitin ligase complex. Thalidomide has been reported to be involved in the regulation of the transcription factor Ikaros by CRBN-mediated degradation. To investigate the nuclear functions of CRBN, we performed co-immunoprecipitation experiments and evaluated the binding of CRBN to Ikaros. As a result, we found that CRBN was associated with Ikaros protein, and the N-terminal region of CRBN was required for Ikaros binding. In luciferase reporter gene experiments, CRBN modulated transcriptional activity of Ikaros. Furthermore, we found that CRBN modulated Ikaros-mediated transcriptional repression of the proenkephalin gene by binding to its promoter region. These results suggest that CRBN binds to Ikaros via its N-terminal region and regulates transcriptional activities of Ikaros and its downstream target, enkephalin.

Identification of a homozygous missense mutation in LRP2 and a hemizygous missense mutation in TSPYL2 in a family with mild intellectual disability.

Non-syndromic autosomal recessive intellectual disability (ID) is a genetically heterogeneous disorder with more than 50 mutated genes to date. ID is characterized by deficits in memory skills and language development with difficulty in learning, problem solving, and adaptive behaviors, and affects ∼ 1% of the population. For detection of disease-causing mutations in such a heterogeneous disorder, homozygosity mapping together with exome sequencing is a powerful approach, as almost all known genes can be assessed simultaneously in a high-throughput manner. In this study, a hemizygous c.786C>G:p.Ile262Met in the testis specific protein Y-encoded-like 2 (TSPYL2) gene and a homozygous c.11335G>A:p.Asp3779Asn in the low-density lipoprotein receptor-related protein 2 (LRP2) gene were detected after genome-wide genotyping and exome sequencing in a consanguineous Pakistani family with two boys with mild ID. Mutations in the LRP2 gene have previously been reported in patients with Donnai-Barrow and Stickler syndromes. LRP2 has also been associated with a 2q locus for autism (AUTS5). The TSPYL2 variant is not listed in any single-nucleotide polymorphism databases, and the LRP2 variant was absent in 400 ethnically matched healthy control chromosomes, and is not listed in single-nucleotide polymorphism databases as a common polymorphism. The LRP2 mutation identified here is located in one of the low-density lipoprotein-receptor class A domains, which is a cysteine-rich repeat that plays a central role in mammalian cholesterol metabolism, suggesting that alteration of cholesterol processing pathway can contribute to ID.

Multiplex PCR Analysis of 17 (11 Novels) STR Markers Linked to Six Autosomal Recessive Intellectual Disability Genes in Iranian Population.

Non-syndromic autosomal recessive intellectual disability (NS-ARID) is a heterogeneous neurodevelopmental disease. More research is needed to study the NS-ARID genes. Using STR markers linked to a specific gene, we can perform homozygosity mapping and prenatal diagnosis. One approach to investigate the NS-ARID genes in large families is homozygosity mapping. In this study, we surveyed allele frequency and allele heterozygosity of 17 NS-ARID STR markers linked to the six NS-ARID genes in Iranian population. The test group consisted of 120 unrelated healthy individuals. STR markers were designed using SERV software. Also, genotyping was done using multiplex PCR. Data was analyzed by Gene Mapper software. Allele frequency and observed heterozygosity rates were estimated using PowerStatV12. Deviation from the Hardy-Weinberg equilibrium (HWE) was performed based on the Exact test. Out of 17 STR loci, 11 were novel. In total, 166 alleles were detected for the 17 markers. According to our study, the D9MAN1B1SD7.4, D19S872, D6GRIK2SI1.7, D19TECRSDI.8, D1ST3GAL3SIO.5, and D14ZC3H14SD5.3 STR loci were found to be the most informative and polymorphic STR markers for MAN1B1, ZNF526, GRIK2, TECR, ST3GAL3, and ZC3H14 genes, respectively. We also performed other statistical analyses on these STR markers and found that all of the 17 STRs were polymorphic and met the Hardy-Weinberg equilibrium. Finding novel STRs, with high allele heterozygosity, is one of the most significant outcomes of the present study. These findings can be useful for homozygosity mapping, PGD, and PND practices for the NS-ARID.

Examining non-syndromic autosomal recessive intellectual disability (NS-ARID) genes for an enriched association with intelligence differences

Two themes are emerging regarding the molecular genetic aetiology of intelligence. The first is that intelligence is influenced by many variants and those that are tagged by common single nucleotide polymorphisms account for around 30% of the phenotypic variation. The second, in line with other polygenic traits such as height and schizophrenia, is that these variants are not randomly distributed across the genome but cluster in genes that work together. Less clear is whether the very low range of cognitive ability (intellectual disability) is simply one end of the normal distribution describing individual differences in cognitive ability across a population. Here, we examined 40 genes with a known association with non-syndromic autosomal recessive intellectual disability (NS-ARID) to determine if they are enriched for common variants associated with the normal range of intelligence differences. The current study used the 3511 individuals of the Cognitive Ageing Genetics in England and Scotland (CAGES) consortium. In addition, a text mining analysis was used to identify gene sets biologically related to the NS-ARID set. Gene-based tests indicated that genes implicated in NS-ARID were not significantly enriched for quantitative trait loci (QTL) associated with intelligence. These findings suggest that genes in which mutations can have a large and deleterious effect on intelligence are not associated with variation across the range of intelligence differences.

Cereblon is recruited to aggresome and shows cytoprotective effect against ubiquitin-proteasome system dysfunction

Cereblon (CRBN) is encoded by a candidate gene for autosomal recessive nonsyndromic intellectual disability (ID). The nonsense mutation, R419X, causes deletion of 24 amino acids at the C-terminus of CRBN, leading to mild ID. Although abnormal CRBN function may be associated with ID disease onset, its cellular mechanism is still unclear. Here, we examine the role of CRBN in aggresome formation and cytoprotection. In the presence of a proteasome inhibitor, exogenous CRBN formed perinuclear inclusions and co-localized with aggresome markers. Endogenous CRBN also formed perinuclear inclusions under the same condition. Treatment with a microtubule destabilizer or an inhibitor of the E3 ubiquitin ligase activity of CRBN blocked formation of CRBN inclusions. Biochemical analysis showed CRBN containing inclusions were high-molecular weight, ubiquitin-positive. CRBN overexpression in cultured cells suppressed cell death induced by proteasome inhibitor. Furthermore, knockdown of endogenous CRBN in cultured cells increased cell death induced by proteasome inhibitor, compared with control cells. Our results show CRBN is recruited to aggresome and has functional roles in cytoprotection against ubiquitin-proteasome system impaired condition.

Frequencies of Six (Five Novel) STR Markers Linked to TUSC3 (MRT7) or NSUN2 (MRT5) Genes Used for Homozygosity Mapping of Recessive Intellectual Disability.

Non-syndromic autosomal recessive intellectual disability (NS-ARID) is an extremely heterogeneous genetic disorder. Therefore, to investigate these genes, more research is required. One approach to investigate the NS-ARID loci is homozygosity mapping which requires appropriate STR markers within or flanking the gene/s of interest. In this research, we aimed to find novel STRs for two common NS-ARID genes (TUSC3 and NSUN2) and, in addition, to identify allele frequencies of those STR markers. The study group included 119 unrelated healthy individuals. STR markers were investigated using the UCSC genome browser web site and SERV software. Genotyping was determined by multiplex PCR. Data were evaluated using Gene Mapper software. Allele frequencies and observed heterozygosity rates were calculated using PowerStatV12. Deviation from Hardy-Weinberg equilibrium and expected heterozygosity were assessed using the DNAView software. In total, 56 alleles were detected. According to our research, D8TUSC3SU8.3 and D5NSUN2SU0.5 were the most informative STR markers in MRT7 and MRT5 loci, respectively and showed a high percentage of heterozygosity in Iranian population. The observed range of allele frequencies was from 3.4% to 32.4% and 0.8% to 18.9% for MRT5 and MRT7 loci, respectively. Further, we have evaluated other statistical surveys of these STR markers and discovered that all of the six listed STRs were informative and five meet the Hardy-Weinberg equilibrium for the tester group. Finding novel STRs, with high allele heterozygosity, is one of the most significant current finding in the present study for the two common NSARID genes. The recognized heterozygosity of these markers make MRT flanking STR markers very efficient to be used in diagnostic medical genetics labs or homozygosity mapping on NS-ARID.