ArticleAmerican journal of human genetics2024
De novo variants in DENND5B cause a neurodevelopmental disorder.
Article in American journal of human genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 8 citations in OpenAlex.
- Traffic Jams in the Brain: How Kinesin Dysfunction Shapes Neurodevelopmental Disorders.Current issues in molecular biology · 2026Review
- Isolated absence epilepsy associated with a de novo FBXW7 missense variant in the F-box domain.Epilepsia open · 2026Article
- Interstitial 12p Deletion Syndrome: Revised Minimal Critical Region and Review of the Literature.Genes · 2026Review
- Variants in DENND2B are associated with vulnerability for neurodevelopmental impairment, psychosis and catatonia.Brain : a journal of neurology · 2026Article
- Role of DENN Domain-Containing Protein 5b (dennd5b) during early embryonic development of zebrafish.Molecular biology reports · 2025Article
- Expanding the phenotypic spectrum of DNM1-related disorders: novel GTPase domain variants and their diverse neurological outcomes.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2025Article
- Chromosomal Location and Identification ofDiagnostics (Basel, Switzerland) · 2025Article
- Novel De Novo RALA Missense Variants Expand the Genotype Spectrum of Hiatt-Neu-Cooper Neurodevelopmental Syndrome.Molecular genetics & genomic medicine · 2025Article
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Authors and funding
37 authors at 14 institutions in 4 countries.
Funding
Abstract
The Rab family of guanosine triphosphatases (GTPases) includes key regulators of intracellular transport and membrane trafficking targeting specific steps in exocytic, endocytic, and recycling pathways. DENND5B (Rab6-interacting Protein 1B-like protein, R6IP1B) is the longest isoform of DENND5, an evolutionarily conserved DENN domain-containing guanine nucleotide exchange factor (GEF) that is highly expressed in the brain. Through exome sequencing and international matchmaking platforms, we identified five de novo variants in DENND5B in a cohort of five unrelated individuals with neurodevelopmental phenotypes featuring cognitive impairment, dysmorphism, abnormal behavior, variable epilepsy, white matter abnormalities, and cortical gyration defects. We used biochemical assays and confocal microscopy to assess the impact of DENND5B variants on protein accumulation and distribution. Then, exploiting fluorescent lipid cargoes coupled to high-content imaging and analysis in living cells, we investigated whether DENND5B variants affected the dynamics of vesicle-mediated intracellular transport of specific cargoes. We further generated an in silico model to investigate the consequences of DENND5B variants on the DENND5B-RAB39A interaction. Biochemical analysis showed decreased protein levels of DENND5B mutants in various cell types. Functional investigation of DENND5B variants revealed defective intracellular vesicle trafficking, with significant impairment of lipid uptake and distribution. Although none of the variants affected the DENND5B-RAB39A interface, all were predicted to disrupt protein folding. Overall, our findings indicate that DENND5B variants perturb intracellular membrane trafficking pathways and cause a complex neurodevelopmental syndrome with variable epilepsy and white matter involvement.
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