This study represents the first application of a Drosophila model to demonstrate that KCNK3 functions as a dosage-sensitive regulator of neurodevelopment and position KCNK3 as a candidate gene for molecular screening and pave the way for future functional studies and therapeutic exploration in NDDs.
Abstract
Neurodevelopmental disorders (NDDs) are a group of developmental brain disorders caused by various genetic or acquired factors. OMIM has only recently associated the KCNK3 gene with developmental delay associated with sleep apnea (DDSA). Most prior studies on the KCNK3 gene have focused on PAH and cardiovascular diseases. In a 2-year-old girl presenting with generalized hypotonia and delayed language development, we identified a de novo missense variant in KCNK3 through the reanalysis of trio-whole exome sequencing (trio-WES) data. To further explore the relationship between KCNK3 and neurodevelopmental phenotypes, we conducted bidirectional expression regulation of the homologous gene Task7 based on the Drosophila model. Both overexpression and knockdown of the Task7 gene induced anxiety-like behaviors and impaired learning and memory. Notably, Task7 overexpression also led to reduced climbing ability and abnormal sleep patterns; collectively, these four phenotypes recapitulate the characteristic hallmarks of human neurodevelopmental disorders. This study represents the first application of a Drosophila model to demonstrate that KCNK3 functions as a dosage-sensitive regulator of neurodevelopment. While the underlying mechanisms remain to be fully elucidated, these findings position KCNK3 as a candidate gene for molecular screening and pave the way for future functional studies and therapeutic exploration in NDDs.
The biological plausibility of LNX2 as a candidate gene for neurodevelopmental disorders is supported, highlighting its preferential association with neuronal projection-cell networks, synaptic vesicle trafficking pathways, and neuron-specific regulatory programs.
M. Vinci, M. Figura, A. Musumeci et al.· Genes· 0 citations
Pathogenic variants in AGO2, encoding a central component of the RNA-induced silencing complex (RISC), cause the neurodevelopmental disorder Lessel-Kreienkamp syndrome (LESKRES). The variant spectrum and associated molecular mechanisms underlying phenotypic variability and disease severity remain incompletely understood. We investigated 45 newly identified individuals carrying 33 distinct AGO2 variants, 30 of which were previously unreported. Phenotypic data from these and previously reported cases (n = 70) were integrated to delineate the LESKRES-associated clinical spectrum and genotype–phenotype correlations. Functional studies included shRNA-based silencing, co-immunoprecipitation, subcellular localization, and sequencing of AGO2-bound miRNAs. All individuals presented with a neurodevelopmental disorder of variable severity. Delayed speech and language development (97%), intellectual disability (97%), and motor delay (93%) were the most consistent features, frequently accompanied by muscular hypotonia, autistic traits, attention deficit hyperactivity disorder, visual impairment and structural brain anomalies. Systemic manifestations, including skeletal, craniofacial, cardiac, and male urogenital anomalies were common, underscoring AGO2’s multisystemic role. Moreover, we report occurrence of gonadal mosaicism and reveal the presence of interfamilial and variant-specific clinical heterogeneity. Variants clustered in defined regions of AGO2, including the L1 loop, helix-7, and multiple loops of the PIWI domain, highlight structural hotspots critical for RISC activity. Not all pathogenic variants impaired shRNA-mediated silencing; this was restricted to p.(Arg714Trp) and p.(Asn729His). Biochemical analyses revealed that p.(Asp619Asn) impaired GW182 binding and P-body assembly. Variants p.(Arg506Gln), p.(Glu531Gln) p.(Gly604Arg) and p.(Asp619Asn), reduced C-terminal phosphorylation, implicating defective AGO2 recycling. AGO2–miRNA co-immunoprecipitation and sequencing demonstrated variant-specific perturbations in miRNA association, strand selectivity, and isomiR generation. Variants near the hinge of the helix-7 region, especially p.(Phe182del), induced extensive changes in miRNA association and 3′-end modification, suggesting impaired anchoring within the miRNA-binding pocket. Our findings substantially broaden the clinical and molecular landscape of LESKRES, establishing AGO2 as a pivotal regulator of neurodevelopment whose structural integrity is essential for precise miRNA-mediated gene regulation. Pathogenic variants disrupt distinct interconnected processes: P-body association, phosphorylation-dependent turnover, and miRNA interactions, culminating in dysregulated post-transcriptional gene silencing. These mechanistic insights link specific structural perturbations in AGO2 to graded clinical outcomes and underscore the critical role of AGO2 conformational dynamics in human neurodevelopment.
Debora Tibbe, Christina Kiel, Olena Ielesicheva et al.· Genome Medicine· 0 citations
The findings implicate DCLK1 in a previously unrecognized progressive neurodevelopmental disorder and demonstrate the power of integrative cross-species functional genomics in resolving ultra-rare disease variants.
Stephen C. Pak, David Butler, Wei-Xi Yuan et al.· Research Square· 0 citations
An integrative study combining Mendelian genetics, clinical and association studies, and animal and molecular modeling supports variants in ELAVL2 as a cause of a neurodevelopmental disorder, with haploinsufficiency as the disease mechanism, and identifies crucial roles of ELAVL2 in neuronal function, cognition, and behavior.
Marina Boon, Meghan R. Mulligan, Jolijn J A Verseput et al.· American Journal of Human Ge...· 0 citations
Current knowledge on the genotypic and phenotypic spectra of SET-NDD is expanded, and pinpoints a smaller 9q34.11 critical region excluding upstream NDD-associated genes, STXBP1 and SPTAN1, implicating SET as a significant NDD-associated gene.
Angelo Condell, Elaine Zhang, Tim Sikora et al.· Clinical Genetics· 0 citations
Objective: To study the Progressive myoclonic epilepsies (PME) that is genetic disorders resulting from mutations in different genes, all characterized by the early onset of myoclonic seizures, and cognitive decline. The Potassium Channel Tetramerization Domain Containing seven (KCTD7) gene encodes for the BRC (broad complex), ttk (tramtrack), and bab/pox virus, and zinc finger domain, containing KCTD7 protein.
Methodology: The study was done in the Center of Excellence in Genomic Medicine and Research (CEGMR). The affected patient, a three-year-old Saudi female born to consanguineous parents, she underwent laboratory tests, EEG assessments, and Whole-Exome Sequencing (WES).
Results: Our results showed a novel five base pair deletion that was detected in homozygous state in the KCTD7 gene. Both the unaffected parents showed heterozygous mutation of the KCTD7 gene. Segregation analysis via Sanger sequencing supported the existence of the homozygous splice donor variant in NM_153033.4:c.493+2_493+6delTGA of KCTD7 gene in the patient.
Conclusion: The mutation is not reported in the literature yet; the particular phenotype that was observed in our patient is comparable to the ones that are described in the KCTD7 related pathologies, combined with segregation analysis indicating both parents carried the variant heterogeneously present is a strong indication that the identified mutation consists of probably pathogenic mutation. This finding will further increase our insight of the genetic basis of PMEs and role of KCTD7 gene mutations in Saudi population.
S. Alharazy, Peter Natesan Pushparaj, Rose Jelani et al.· Pakistan Journal of Medical...· 0 citations