This study provides substantial evidence for the vital role of trip12 in the early stages of development, as homozygous individuals exhibited early mortality by Day 23 post-fertilization, while a substantial mortality rate was observed by Day 35 in ‘heterozygous’ mutants.
Abstract
Abstract Thyroid Hormone Receptor Interactor 12 (TRIP12) is an E3 ubiquitin ligase capable of mediating ubiquitin-dependent proteolysis of specific protein substrates. This function regulates key biological processes, including cell cycle progression, cell differentiation, chromatin remodelling and DNA damage repair. Consequently, loss-of-function mutations in TRIP12 have been associated with a broad spectrum of human diseases, including cancer and neurological and neurodevelopmental disorders. Previous studies have demonstrated that pathological variants of TRIP12 cause Clark–Baraitser syndrome, characterized by craniofacial dysmorphism, motor delay and intellectual disability, with or without autism spectrum disorder. Despite the well-characterized clinical manifestations, the underlying molecular pathways affected by TRIP12 disruption and their implication in the pathophysiology of autism spectrum disorder and intellectual disability remain unclear. Using a knock-out zebrafish model, we have elucidated the essential role of trip12 in diverse metabolic and biological pathways, particularly those related to neural and neurodevelopmental processes, shedding light on potential mechanisms underlying the pathogenesis. Heterozygous and recessive homozygous zebrafish mutants exhibit clinical features analogous to those observed in human patients, including craniofacial anomalies and decreased locomotor activity. Furthermore, this study provides substantial evidence for the vital role of trip12 in the early stages of development, as homozygous individuals exhibited early mortality by Day 23 post-fertilization, while a substantial mortality rate of 90% was observed by Day 35 in ‘heterozygous’ mutants. The present study demonstrates the profound impact that trip12 mutations have on embryogenesis, and transcriptomic analysis offers an in-depth knowledge of the molecular basis of the disease. These findings offer valuable insights into potential therapeutic targets for improving outcomes in individuals with TRIP12-associated disorders.
Evidence is provided that biallelic GIT1 variants affecting transcript processing or causing premature termination underlie a syndromic neurodevelopmental disorder and an essential role for GIT1 in development and cognitive function is established.
P. Failla, V. Muto, Antonella Lauri et al.· Brain : a journal of neurolo...· 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
Combined transcriptomics profiling in cyp2u1-/- zebrafish and SPG56 patient iPSC-derived cortical neurons supports impaired neural network development as a key disease mechanism.
D. Galatolo, Devid Damiani, V. Naef et al.· Human Molecular Genetics· 0 citations
INTRODUCTION
DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) is a dosage-sensitive regulator of central nervous system development. Dysregulation contributes to major neurodevelopmental disorders, including Down Syndrome (DS), Autism Spectrum Disorder (ASD), and Intellectual Developmental Disorder (IDD). This review critically examines how DYRK1A dosage shapes neurodevelopment, neurotransmitter regulation, and disease phenotypes.
METHODS
We synthesized molecular, cellular, and systems-level evidence (2015-2025) from rodent DYRK1A mutant models, human iPSC-derived neural progenitors, and human transcriptomic datasets using comprehensive searches of PubMed, Google Scholar, and Web of Science. Studies were assessed for mechanistic rigor, species applicability, and translational potential.
RESULTS
Recent studies reveal that DYRK1A coordinates four neurodevelopmental processes: (1) neural progenitor proliferation/differentiation via cell cycle regulation (cyclin D1, p27Kip1, E2F2, NeuroD1); (2) chromatin remodeling through histone acetyltransferase phosphorylation (EP300, CREBBP); (3) glutamatergic synaptic transmission via presynaptic gene suppression (RIMS1, Munc13-1, Syn2), impairing NMDA-independent long-term potentiation; (4) glial differentiation and myelination. DYRK1A overexpression in DS disrupts neurogenesis and synaptic connectivity; haploinsufficiency causes microcephaly and intellectual disability. Species divergence between rodent and human iPSC models, combined with inter-individual variability, underscores the limitations of current mechanistic models.
DISCUSSION
DYRK1A functions as a dosage‑sensitive regulator orchestrating neurogenesis, chromatin remodeling, synaptic transmission, and glial maturation. Evidence from rodent and human iPSC models underscores mechanistic divergence and inter‑individual variability, complicating translational pathways. Therapeutic strategies, such as small‑molecule inhibitors, CRISPR‑Cas9, and antisense oligonucleotides, show promise but require precise titration to restore equilibrium. Personalized iPSC models, biomarker development, and longitudinal monitoring remain essential for advancing precision medicine approaches targeting dosage‑sensitive genes like DYRK1A.
CONCLUSION
Therapeutic strategies, such as small-molecule inhibitors (EGCG, harmine), CRISPR-Cas9, and antisense oligonucleotides, demonstrate preclinical efficacy but require precise dosage titration to restore physiological equilibrium without disrupting neurogenic processes. Clinical translation necessitates personalized iPSC models, biomarkers, and longitudinal monitoring. DYRK1A exemplifies precision medicine for dosage-sensitive genes where therapeutic success depends on restoring physiological balance.
Variants in BRSK2, encoding brain specific kinase-2, have recently been associated with an autosomal dominant neurodevelopmental disorder (NDD). We have assembled 52 cases with heterozygous BRSK2 variants and variable neurodevelopmental phenotypes with frequent neuropsychiatric and behavioral symptoms. The variant spectrum included 15 different truncating variants, seven (potential) splice variants, three structural variants, and 12 different missense variants. Of the missense variants, seven were in the kinase domain, and the others in the UBA and the KA1 domain or outside domains. Variants occurred de novo in 19 cases and were inherited in 18. We utilized Drosophila melanogaster as a model and assessed viability and performed climbing and bang sensitivity assays upon knockdown of the fly orthologue sff or upon overexpression of wildtype or mutant human BRSK2. Pan-neuronal knockdown of sff resulted in impaired locomotor behavior and seizure susceptibility. Ubiquitous or pan-neuronal overexpression of human wildtype BRSK2 in Drosophila resulted in lethality or locomotor impairment, respectively, indicating toxicity. Overexpressing mutant BRSK2 did not or incompletely affect viability and locomotor behavior for six of seven tested kinase domain missense variants and one KA1 domain variant, indicating a (partial) loss-of-function effect. Interestingly, overexpressing BRSK2 with the remaining missense variant from the kinase domain and the two most C-terminal missense variants resulted in possible gain of function. Our findings further delineate the clinical and molecular spectrum of BRSK2-associated NDD and provide further insights into the role of BRSK2/sff in nervous system function and dysfunction.
Palak Singhal, Tzung-Chien Hsieh, Nadja Ehmke et al.· European Journal of Human Ge...· 0 citations