Biology subjects

Kuismin, O.

Publications and source records attributed to Kuismin, O..

7 recordsLinked to original sources

bioRxiv2026

INTS6 loss of function disrupts transcriptional regulation in mild intellectual disability

Pathogenic variants in genes involved in transcriptional regulation and RNA processing have emerged as points of functional convergence in neurodevelopmental disorders (NDDs), but their specific disease mechanisms remain unknown. By screening 1,562 Finnish extended families from the Northern Finland Intellectual Disability cohort affected by cognitive impairment, we discovered a family with six affected members carrying a heterozygous loss- of-function variant in INTS6. INTS6 is a conserved member of the phosphatase module of the Integrator complex, which regulates RNA polymerase II activity, with a reported role in the pathogenesis of NDDs. To determine the variants transcriptomic effects, we performed RNA-sequencing of induced pluripotent stem cells (iPSCs) and iPSC-derived neuronal cells from cases and controls, revealing transcriptome-wide splicing defects, with increased intron retention observed in genes involved in translation, cell cycle and RNA processing in variant carriers. CRISPR-Cas9 knock-in iPSCs confirmed that the variant was associated with downregulation of transcription factors and developmental processes in early neuron differentiation. In addition, downregulated genes in variant carrier neurons were enriched for synaptic genes, suggesting effects on neuronal development. These findings highlight the critical role of INTS6 in transcriptional regulation of human neurodevelopment and reinforce its association with NDDs.

genetics↗

bioRxiv2026

ARID5B mutations cause a neurodevelopmental syndrome with neuroinflammation episodes

Genetic disorders affecting the epigenetic machinery constitute a major group of neurodevelopmental conditions. Pathogenic variants in several ARID transcription factors--particularly ARID1A, ARID1B, and ARID2--cause Coffin-Siris syndromes, all characterized by intellectual disability (ID). These genes encode core subunits of the BRG1/BRM-associated factor (BAF) chromatin remodeling complex. In contrast, ARID family members that function in other regulatory complexes have remained largely unexplored in neurodevelopmental disease. Here, we identify 29 individuals carrying heterozygous ARID5B variants, of which 24 (83%) introduce premature termination codons in the exceptionally long final exon, one affects the exon 9 splice donor site, and four are missense variants in conserved domains within the N-terminal half of the protein. Using a CRISPR-Cas9 knock-in mouse model harboring the p.Q522Ter variant, together with in vitro assays, we investigated the functional consequences of C-terminal ARID5B truncations. All affected individuals presented with global developmental delay or ID--most commonly mild--and frequent speech and language impairment. Recurrent features included kidney malformations, behavioral difficulties, and recurrent infections of the respiratory and urinary tracts. Two individuals experienced central nervous system inflammation, and two infants presented with persistent pulmonary hypertension. Remarkably, 19 of 29 variants (66%) cluster within the first quarter of exon 10, are de novo, and escape nonsense-mediated mRNA decay (NMD), which we confirmed for two variants affecting seven individuals. Variants outside this region were inherited. Heterozygous mice exhibited developmental and behavioral abnormalities, while homozygous mutations was perinatally lethal. Truncations and a small deletion within a predicted nuclear localization signal (NLS) caused cytosolic mislocalization of ARID5B, whereas the isolated C-terminal half retained nuclear localization, suggesting an independent distal NLS. Collectively, these findings define ARID5B-related neurodevelopmental disorder as a distinct clinical entity and reveal how disruption of specific ARID5B domains impacts protein localization, mammalian development, immune and neurobehavioral function. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=108 SRC="FIGDIR/small/698931v1_ufig1.gif" ALT="Figure 1"> View larger version (29K): org.highwire.dtl.DTLVardef@158e8d9org.highwire.dtl.DTLVardef@1f014dorg.highwire.dtl.DTLVardef@18e6e7forg.highwire.dtl.DTLVardef@1f886e9_HPS_FORMAT_FIGEXP M_FIG C_FIG

genetics↗

bioRxiv2024

Dsg2 truncation causes a lethal barrier breakdown in mice

Inflammatory bowel diseases (IBD) such as Crohns disease (CD) have a complex aetiology with alterations of both the intestinal epithelial barrier and the IL23/IL17 immune response. Here, we investigated the role of a novel mutation in the desmosomal cadherin desmoglein 2 gene (DSG2) in the pathogenesis of IBD. DSG2 is known to regulate intestinal epithelial barrier integrity. Genetic analysis of a CD patient revealed a novel likely pathogenic DSG2 mutation leading to a truncated protein lacking part of the intracellular domain. We generated an enterocyte-specific mouse model, recapitulating the human mutation to study how the cytoplasmic truncation of Dsg2 affects intestinal barrier properties systemically. Moreover, we analysed the intestinal genetic profile in these mice and compared it to IBD patients. We describe a first CD patient with a rare mutation in the DSG2 gene causing cytoplasmic truncation with affects Dsg2 mobility. Mice with enterocyte-specific Dsg2 truncation suffered from a lethal intestinal barrier defect and presented a skewed IL17 response similar to CD patients. We identified the desmosomal cadherin Dsg2 as a regulator of the skewed IL17 response. These data indicate that desmosomes regulate inflammation similar to psoriasis which explains why the same novel immune therapies are effective for both diseases.

cell biology↗

bioRxiv2021

The 22q11.2 region regulates presynaptic gene-products linked to schizophrenia

To study how the 22q11.2 deletion predisposes to psychiatric disease, we generated induced pluripotent stem cells from deletion carriers and controls, as well as utilized CRISPR/Cas9 to introduce the heterozygous deletion into a control cell line. Upon differentiation into neural progenitor cells, we found the deletion acted in trans to alter the abundance of transcripts associated with risk for neurodevelopmental disorders including Autism Spectrum Disorder. In more differentiated excitatory neurons, altered transcripts encoded presynaptic factors and were associated with genetic risk for schizophrenia, including common (per-SNP heritability p ({tau}c)= 4.2 x 10-6) and rare, loss of function variants (p = 1.29x10-12). These findings suggest a potential relationship between cellular states, developmental windows and susceptibility to psychiatric conditions with different ages of onset. To understand how the deletion contributed to these observed changes in gene expression, we developed and applied PPItools, which identifies the minimal protein-protein interaction network that best explains an observed set of gene expression alterations. We found that many of the genes in the 22q11.2 interval interact in presynaptic, proteasome, and JUN/FOS transcriptional pathways that underlie the broader alterations in psychiatric risk gene expression we identified. Our findings suggest that the 22q11.2 deletion impacts genes and pathways that may converge with risk loci implicated by psychiatric genetic studies to influence disease manifestation in each deletion carrier.

neuroscience↗

bioRxiv2018

Haploinsufficiency of A20 impairs protein-protein interactome and leads into caspase-8-dependent enhancement of NLRP3 inflammasome activation

ObjectivesTNFAIP3 encodes A20 that negatively regulates nuclear factor kappa light chain enhancer of activated B cells (NF-{kappa}B), the major transcription factor coordinating inflammatory gene expression. TNFAIP3 polymorphisms have been linked with a spectrum of inflammatory and autoimmune diseases and recently, loss-of-function mutations in A20 were found to cause a novel inflammatory disease haploinsufficiency of A20 (HA20). Here we describe a family with HA20 caused by a novel TNFAIP3 loss-of-function mutation and elucidate the upstream molecular mechanisms linking HA20 to dysregulation of NF-{kappa}B and the related inflammasome pathway.\n\nMethodsNF-{kappa}B activation was studied in a mutation-expressing cell line using luciferase reporter assay. Physical and close-proximity protein-protein interactions of wild-type and TNFAIP3 p.(Lys91*) mutant A20 were analyzed using mass spectrometry. NF-{kappa}B -dependent transcription, cytokine secretion, and inflammasome activation were compared in immune cells of the HA20 patients and control subjects.\n\nResultsThe protein-protein interactome of p.(Lys91*) mutant A20 was severely impaired, including inter-actions with proteins regulating NF-{kappa}B activation, DNA repair responses, and the NLR family pyrin domain containing 3 (NLRP3) inflammasome. The p.(Lys91*) mutant A20 failed to suppress NF-{kappa}B signaling, which led to increased NF-{kappa}B -dependent proinflammatory cytokine transcription. Functional experiments in the HA20 patients immune cells uncovered a novel caspase-8-dependent mechanism of NLRP3 inflammasome hyperresponsiveness that mediated the excessive secretion of interleukin-1{beta} and -18.\n\nConclusionsThe current findings significantly deepen our understanding of the molecular mechanisms underlying HA20 and other diseases associated with reduced A20 expression or function, paving the way for future therapeutic targeting of the pathway.

molecular biology↗

bioRxiv2018

Contribution of rare and common variants to intellectual disability in a high-risk population sub-isolate of Northern Finland

The contribution of de novo and ultra-rare genetic variants in severe and moderate intellectual disability (ID) has been extensively studied whereas the genetic architecture of mild ID has been less well characterized. To elucidate the genetic background of milder ID we studied a regional cohort of 442 ID patients enriched for mild ID (>50%) from a population isolate of Finland. We analyzed rare variants using exome sequencing and CNV genotyping and common variants using common variant polygenic risk scores. As controls we used a Finnish collection of exome sequenced (n=11311) and GWAS chip genotyped (n=11699) individuals.\n\nWe show that rare damaging variants in genes known to be associated with cognitive defects are observed more often in severe (27%) than in mild ID (13%) patients (p-value: 7.0e-4). We further observed a significant enrichment of protein truncating variants in loss-of-function intolerant genes, as well as damaging missense variants in genes not yet associated with cognitive defects (OR: 2.1, p-value: 3e-8). For the first time to our knowledge, we show that a common variant polygenic load significantly contributes to all severity forms of ID. The heritability explained was the highest for educational attainment (EDU) in mild ID explaining 2.2% of the heritability on liability scale. For more severe ID it was lower at 0.6%. Finally, we identified a homozygote variant in the CRADD gene to be a cause of a specific syndrome with ID and pachygyria. The frequency of this variant is 50x higher in the Finnish population than in non-Finnish Europeans, demonstrating the benefits of utilizing population isolates in rare variant analysis of diseases under negative selection.

genetics↗

bioRxiv2017

Quantifying the impact of rare and ultra-rare coding variation across the phenotypic spectrum

There is a limited understanding about the impact of rare protein truncating variants across multiple phenotypes. We explore the impact of this class of variants on 13 quantitative traits and 10 diseases using whole-exome sequencing data from 100,296 individuals. Protein truncating variants in genes intolerant to this class of mutations increased risk of autism, schizophrenia, bipolar disorder, intellectual disability, ADHD. In individuals without these disorders, there was an association with shorter height, lower education, increased hospitalization and reduced age. Gene sets implicated from GWAS did not show a significant protein truncating variants-burden beyond what captured by established Mendelian genes. In conclusion, we provide the most thorough investigation to date of the impact of rare deleterious coding variants on complex traits, suggesting widespread pleiotropic risk.\n\nMain abbreviations

genetics↗