ArticleAmerican journal of human genetics2020
Bi-allelic Variants in RALGAPA1 Cause Profound Neurodevelopmental Disability, Muscular Hypotonia, Infantile Spasms, and Feeding Abnormalities.
Article in American journal of human genetics, 2020. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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20 citing papers in PubMed, 34 citations in OpenAlex.
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- Genome-wide Genetic Mutations Accumulated in Pigs Genome-edited for Xenotransplantation and Their Filial Generation.Genomics, proteomics & bioinformatics · 2025Article
- Genetic Architecture of Cerebral White Matter Hyperintensities in Diverse Hispanic/Latino Adults.Neurology. Genetics · 2025Article
- RalGAP complexes control secretion and primary cilia in pancreatic disease.Life science alliance · 2025Article
- Structure and mechanism of the RalGAP tumor suppressor complex.Nature communications · 2025Article
- CHIRP-Seq: FOXP2 transcriptional targets in zebra finch brain include numerous speech and language-related genes.BMC neuroscience · 2025Article
- Identification of SURF4 and RALGAPA1 as promising therapeutic targets in glioblastoma and pan-cancer through integrative multi-omics, CRISPR-Cas9 screening and prognostic meta-analysis.Cancer immunology, immunotherapy : CII · 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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- Deciphering the population structure and genetic basis of growth traits from whole-genome resequencing of the leopard coral grouper (Zoological research · 2024Article
- Haploinsufficiency ofIntractable & rare diseases research · 2024Article
- The landscape of SETBP1 gene expression and transcription factor activity across human tissues.PloS one · 2024Article
- Analysis of the serum proteome profile of wild stump-tailed macaques (Frontiers in veterinary science · 2024Article
- The landscape ofbioRxiv : the preprint server for biology · 2023Article
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- Regulation of cargo exocytosis by a Reps1-Ralbp1-RalA module.Science advances · 2023Article
- Rare CNVs and Known Genes Linked to Macrocephaly: Review of Genomic Loci and Promising Candidate Genes.Genes · 2022Review
- Dysregulation of RalA signaling through dual regulatory mechanisms exerts its oncogenic functions in hepatocellular carcinoma.Hepatology (Baltimore, Md.) · 2022Article
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Authors and funding
25 authors at 11 institutions in 4 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Ral (Ras-like) GTPases play an important role in the control of cell migration and have been implicated in Ras-mediated tumorigenicity. Recently, variants in RALA were also described as a cause of intellectual disability and developmental delay, indicating the relevance of this pathway to neuropediatric diseases. Here, we report the identification of bi-allelic variants in RALGAPA1 (encoding Ral GTPase activating protein catalytic alpha subunit 1) in four unrelated individuals with profound neurodevelopmental disability, muscular hypotonia, feeding abnormalities, recurrent fever episodes, and infantile spasms . Dysplasia of corpus callosum with focal thinning of the posterior part and characteristic facial features appeared to be unifying findings. RalGAPA1 was absent in the fibroblasts derived from two affected individuals suggesting a loss-of-function effect of the RALGAPA1 variants. Consequently, RalA activity was increased in these cell lines, which is in keeping with the idea that RalGAPA1 deficiency causes a constitutive activation of RalA. Additionally, levels of RalGAPB, a scaffolding subunit of the RalGAP complex, were dramatically reduced, indicating a dysfunctional RalGAP complex. Moreover, RalGAPA1 deficiency clearly increased cell-surface levels of lipid raft components in detached fibroblasts, which might indicate that anchorage-dependence of cell growth signaling is disturbed. Our findings indicate that the dysregulation of the RalA pathway has an important impact on neuronal function and brain development. In light of the partially overlapping phenotype between RALA- and RALGAPA1-associated diseases, it appears likely that dysregulation of the RalA signaling pathway leads to a distinct group of genetic syndromes that we suggest could be named RALopathies.
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