ArticleAmerican journal of human genetics2013
Yunis-Varón syndrome is caused by mutations in FIG4, encoding a phosphoinositide phosphatase.
Article in American journal of human genetics, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 85 papers, 1 of them a synthesis that pooled it.
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Who cites it
85 citing papers in PubMed, 1 synthesis or guideline pooled it, 141 citations in OpenAlex.
- Neuropathology of genetically defined malformations of cortical development-A systematic literature review.Neuropathology and applied neurobiology · 2021Pooled it
- Whole-Exome Sequencing Reveals the Genetic Landscape and Genotype-Phenotype Spectrum of Dystonia in a Chinese Cohort.CNS neuroscience & therapeutics · 2026Article
- Expanding Spectrum of FIG4-Related Neurological Disorders of Lysosomal Homeostasis: Case Report and Overview of the Potential Genotype-Phenotype Correlations.Clinical genetics · 2026Review
- The multifaceted significance of phosphoinositides in endocytic trafficking.FEBS letters · 2026Review
- Autophagy-lysosomal pathway in neurodegeneration.Molecular neurodegeneration advances · 2026Review
- Disruption of the PIKfyve complex unveils an adaptive mechanism to promote lysosomal repair and mitochondrial homeostasis.Nature communications · 2025Article
- Homeostatic Influence of Fig4 Outside of the Fab1-Vac14-Fig4 Complex in Saccharomyces cerevisiae.Molecular microbiology · 2025Article
- Bergeyella cardium variant induces a unique cytoplasmic vacuolization cell death floatptosis in macrophage.Cell discovery · 2025Article
- Not So Smooth Sailing: FIG4-Related Disease Is a Differential Diagnosis of Rapid Onset Dystonia-Parkinsonism.Movement disorders clinical practice · 2025Article
- VAC14 oligomerization is essential for the function of the FAB1/PIKfyve-VAC14-FIG4 complex.Molecular biology of the cell · 2025Article
- A lipid metabolism related gene signature predicts postoperative recurrence in pancreatic cancer through multicenter cohort validation.Scientific reports · 2025Article
- Phosphoinositide Metabolism: Biochemistry, Physiology and Genetic Disorders.Journal of inherited metabolic disease · 2025Review
- Identification and splicing analysis of the first deep intronicFrontiers in genetics · 2025Article
- Repeated evolution on oceanic islands: comparative genomics reveals species-specific processes in birds.BMC ecology and evolution · 2024Article
- The Cleft palate-craniofacial journal : official publication of the American Cleft Palate-Craniofacial Association · 2024Review
- FIG4-associated disease manifesting as rapidly progressive amyotrophic lateral sclerosis.Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology · 2024Article
- Clinical and genetic features of patients suffering from CMT4J.Journal of neurology · 2024Article
- Exploring the phenotypic spectrum and osteopenia mechanisms in Yunis-Varón syndrome.Genetics in medicine open · 2024Article
- The endolysosomal pathway and ALS/FTD.Trends in neurosciences · 2023Review
- The signalling lipid PI3,5POpen biology · 2023Article
25 more citing papers are in PubMed but not listed here.
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Authors and funding
16 authors at 10 institutions in 8 countries.
Funding
Abstract
Yunis-Varón syndrome (YVS) is an autosomal-recessive disorder with cleidocranial dysplasia, digital anomalies, and severe neurological involvement. Enlarged vacuoles are found in neurons, muscle, and cartilage. By whole-exome sequencing, we identified frameshift and missense mutations of FIG4 in affected individuals from three unrelated families. FIG4 encodes a phosphoinositide phosphatase required for regulation of PI(3,5)P(2) levels, and thus endosomal trafficking and autophagy. In a functional assay, both missense substitutions failed to correct the vacuolar phenotype of Fig4-null mouse fibroblasts. Homozygous Fig4-null mice exhibit features of YVS, including neurodegeneration and enlarged vacuoles in neurons. We demonstrate that Fig4-null mice also have small skeletons with reduced trabecular bone volume and cortical thickness and that cultured osteoblasts accumulate large vacuoles. Our findings demonstrate that homozygosity or compound heterozygosity for null mutations of FIG4 is responsible for YVS, the most severe known human phenotype caused by defective phosphoinositide metabolism. In contrast, in Charcot-Marie-Tooth disease type 4J (also caused by FIG4 mutations), one of the FIG4 alleles is hypomorphic and disease is limited to the peripheral nervous system. This genotype-phenotype correlation demonstrates that absence of FIG4 activity leads to central nervous system dysfunction and extensive skeletal anomalies. Our results describe a role for PI(3,5)P(2) signaling in skeletal development and maintenance.
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