AI-MARRVEL — A Knowledge-Driven AI System for Diagnosing Mendelian Disorders

NEJM AI, Journal Year: 2024, Volume and Issue: 1(5)

Published: April 25, 2024

Diagnosing genetic disorders requires extensive manual curation and interpretation of candidate variants, a labor-intensive task even for trained geneticists. Although artificial intelligence (AI) shows promise in aiding these diagnoses, existing AI tools have only achieved moderate success primary diagnosis.

Language: Английский

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The epilepsy–autism phenotype associated with developmental and epileptic encephalopathies: New mechanism‐based therapeutic options

Epilepsia, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 22, 2025

Abstract Epilepsy and autism often co‐occur in genetic developmental epileptic encephalopathies (DEEs), but their underlying neurobiological processes remain poorly understood, complicating treatment. Advances molecular genetics understanding the neurodevelopmental pathogenesis of epilepsy–autism phenotype may lead to mechanism‐based treatments for children with DEEs autism. Several genes, including newly reported PPFIA3 , MYCBP2 DHX9 TMEM63B RELN are linked various disorders, intellectual disabilities, autistic features. These findings underscore clinical heterogeneity suggest diverse mechanisms influenced by genetic, epigenetic, environmental factors. Mechanisms linking epilepsy include γ‐aminobutyric acidergic (GABAergic) signaling dysregulation, synaptic plasticity, disrupted functional connectivity, neuroinflammatory responses. GABA system abnormalities, critical inhibitory neurotransmission, contribute both conditions. Dysregulation mechanistic target rapamycin (mTOR) pathway neuroinflammation also pivotal, affecting seizure generation, drug resistance, neuropsychiatric comorbidities. Abnormal function connectivity further phenotype. New treatment options targeting specific emerging. Genetic variants potassium channel genes like KCNQ2 KCNT1 frequent causes early onset DEEs. Personalized retigabine quinidine have been explored heterogeneous Efforts ongoing develop more effective KCNQ activators blockers. SCN1A variants, particularly Dravet syndrome, show potential symptoms low‐dose clonazepam, fenfluramine, cannabidiol, although human trials yet consistently replicate animal model successes. Early intervention before age 3 years, ‐ tuberous sclerosis complex‐related DEEs, is crucial. Additionally, mTOR shows promise control managing epilepsy‐associated Understanding distinct spectrum disorder implementing behavioral interventions essential improving outcomes. Despite advances, significant challenges persist diagnosing treating DEE‐associated phenotypes. Future should adopt precision health approaches improve

Language: Английский

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The clinical utility and diagnostic implementation of human subject cell transdifferentiation followed by RNA sequencing

The American Journal of Human Genetics, Journal Year: 2024, Volume and Issue: 111(5), P. 841 - 862

Published: April 8, 2024

Language: Английский

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Ubiquitin ligase and signalling hub MYCBP2 is required for efficient EPHB2 tyrosine kinase receptor function

eLife, Journal Year: 2024, Volume and Issue: 12

Published: Jan. 30, 2024

Eph receptor tyrosine kinases participate in a variety of normal and pathogenic processes during development throughout adulthood. This versatility is likely facilitated by the ability receptors to signal through diverse cellular signalling pathways: primarily controlling cytoskeletal dynamics, but also regulating growth, proliferation, survival. Despite many proteins linked these pathways interacting with receptors, specific mechanisms behind such links their coordination remain be elucidated. In proteomics screen for novel EPHB2 multi-effector proteins, we identified human MYC binding protein 2 (MYCBP2 or PAM Phr1). MYCBP2 large hub involved as neuronal connectivity, synaptic cell division, survival, ubiquitination. Our biochemical experiments demonstrate that formation complex containing FBXO45, known select substrates ubiquitin ligase activity. Formation MYCBP2-EPHB2 does not require kinase activity destabilised ephrin-B ligands, suggesting association prelude signalling. Paradoxically, loss results increased ubiquitination decrease its levels stabilises EPHB2. Commensurate this effect, our reveal essential efficient responses lines primary neurons. Finally, genetic studies Caenorhabditis elegans provide vivo evidence ephrin VAB-1 displays interactions proteins. Together, align similarity neurodevelopmental phenotypes caused function, couple effector controls functions.

Language: Английский

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The Drosophila ZNRF1/2 homologue, detour, interacts with HOPS complex and regulates autophagy

Communications Biology, Journal Year: 2024, Volume and Issue: 7(1)

Published: Feb. 15, 2024

Abstract Autophagy, the process of elimination cellular components by lysosomal degradation, is essential for animal development and homeostasis. Using autophagy-dependent Drosophila larval midgut degradation model we identified an autophagy regulator, RING domain ubiquitin ligase CG14435 (detour). Depletion detour resulted in increased early-stage autophagic vesicles, premature tissue contraction, overexpression or mammalian homologues, ZNRF1 ZNRF2, vesicle size. The ablation ZNRF2 cells basal autophagy. We interacting proteins including HOPS subunits, deep orange (dor/VPS18), Vacuolar protein sorting 16A (VPS16A), light (lt/VPS41) found that promotes their ubiquitination. mutant accumulated autophagy-related young adults, displayed ageing, impaired motor function, activation innate immunity. Collectively, our findings suggest a role autophagy, likely through regulation complex, with implications healthy aging.

Language: Английский

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Fkbp5 gene deletion: Circadian rhythm profile and brain proteomics in aged mice

Aging Cell, Journal Year: 2024, Volume and Issue: unknown

Published: Sept. 3, 2024

Abstract FKBP51, also known as FK506‐binding protein 51, is a molecular chaperone and scaffolding with significant roles in regulating hormone signaling responding to stress. Genetic variants FKBP5 , which encodes have been implicated growing number of neuropsychiatric disorders, has spurred efforts target FKBP51 therapeutically. However, the mechanisms sub‐anatomical regions influenced by these disorders are not fully understood. In this study, we aimed examine impact Fkbp5 ablation using circadian phenotyping analyses. Our findings revealed that lack did significantly alter rhythms, detected wheel‐running activity, but offer protection against stress‐mediated disruptions rhythmicity sex‐dependent manner. Protein changes KO mice, measured histology proteomics, alterations brain region‐ Notably, regardless sex, aged KOs showed elevated MYCBP2, FBXO45, SPRYD3 levels, associated neuronal‐cell adhesion synaptic integrity. Additionally, pathways such serotonin receptor S100 family were differentially regulated mice. Weighted correlation network analysis identified networks linked transmission neuroinflammation. The information generated work can be used better understand during aging absence implications for continued development FKBP51‐focused therapeutics stress‐related disorders.

Language: Английский

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An update on autophagy disorders

Journal of Inherited Metabolic Disease, Journal Year: 2024, Volume and Issue: unknown

Published: Oct. 17, 2024

Abstract Macroautophagy is a highly conserved cellular pathway for the degradation and recycling of defective cargo including proteins, organelles, macromolecular complexes. As autophagy particularly relevant homeostasis in post‐mitotic tissues, congenital disorders autophagy, due to monogenic defects key genes, share common “clinical signature” neurodevelopmental, neurodegenerative, neuromuscular features, as well variable abnormalities eyes, skin, heart, bones, immune cells, other organ systems, depending on expression pattern specific function proteins. Since clinical genetic resolution EPG5 ‐related Vici syndrome, paradigmatic disorder widespread use massively parallel sequencing has resulted identification growing number autophagy‐associated disease encoding members core machinery related Recently identified linking selective vesicular trafficking, pathways have further expanded molecular phenotypical spectrum spectrum. Moreover, significant advances basic research enhanced understanding underlying pathophysiology basis therapy development. Here, we review (i) context intracellular trafficking pathways; (ii) main their typical clinico‐pathological signatures; (iii) recommended primary health surveillance based available evidence. We discuss recently mechanisms that inform current disease, perspectives future therapeutic approaches.

Language: Английский

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MYCBP2-mediated HNF4α ubiquitination reprogrammed lipid metabolism in MASH-associated hepatocellular carcinoma

Oncogene, Journal Year: 2025, Volume and Issue: unknown

Published: April 3, 2025

Language: Английский

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First Report of an Inherited MYCBP2 Neurodevelopmental Disorder: Review of Proband and Parent Presentation

Research Square (Research Square), Journal Year: 2025, Volume and Issue: unknown

Published: May 7, 2025

MYCBP2-associated neurodevelopmental disorder is an autosomal dominant genetic disorder, previously described with de novo variants. We present the case of a two-generation review proband maternally inherited heterozygous pathogenic variant in MYCBP2, c.4409dup (p.Leu1470Phefs*7). Neuropsychology assessment indicated developmental delays proband’s scores falling well below age-level expectations, while mother demonstrated generally intact cognition evidence subtle executive inefficiency. Assessment parental genotype and phenotype can help to anticipate child’s trajectory, especially disorders associated highly variable expressivity. However information gaps on familial impact across generations remain.

Language: Английский

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Molecular regulation of axon termination in mechanosensory neurons

Development, Journal Year: 2024, Volume and Issue: 151(17)

Published: Sept. 1, 2024

ABSTRACT Spatially and temporally accurate termination of axon outgrowth, a process called termination, is required for efficient, precise nervous system construction wiring. The mechanosensory neurons that sense low-threshold mechanical stimulation or gentle touch have proven exceptionally valuable studying over the past 40 years. In this Review, we discuss progress made in deciphering molecular genetic mechanisms govern receptor neurons. Findings across model organisms, including Caenorhabditis elegans, Drosophila, zebrafish mice, revealed complex signaling with conserved principles players beginning to surface. A key emerging theme mediated by networks include ubiquitin ligase hubs, kinase cascades, transcription factors, guidance/adhesion receptors growth factors. Here, begin discussion about how these could represent codes trigger cessation outgrowth different species types

Language: Английский

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