ArticleAmerican journal of human genetics2014
The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.
Article in American journal of human genetics, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 71 papers.
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Who cites it
71 citing papers in PubMed, 99 citations in OpenAlex.
- Alu-mediated SPAST deletion impairs golgi zinc transport and reveals a druggable vulnerability.Signal transduction and targeted therapy · 2026Article
- Widespread distribution of Alu/Alu-mediated genomic rearrangement predisposing to a broad range of Mendelian disease and cancer in human populations.Genome medicine · 2026Article
- Multi-ancestry GWAS reveals loci linked to human variation in LINE-1- and Alu-insertion numbers.bioRxiv : the preprint server for biology · 2025Article
- Multi-ancestry GWAS reveals loci linked to human variation in LINE-1- and Alu-insertion numbers.Translational medicine of aging · 2025Article
- Article
- A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.Chromosome research : an international journal on the molecular, supramolecular and evolutionary aspects of chromosome biology · 2024Article
- LDLR gene rearrangements in Czech FH patients likely arise from one mutational event.Lipids in health and disease · 2024Article
- A heterozygous germline deletion within USP8 causes severe neurodevelopmental delay with multiorgan abnormalities.Journal of human genetics · 2024Article
- A germline chimeric KANK1-DMRT1 transcript derived from a complex structural variant is associated with a congenital heart defect segregating across five generations.Research square · 2023Article
- Meiotic DNA breaks drive multifaceted mutagenesis in the human germ line.Science (New York, N.Y.) · 2023Article
- Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review.Molecular syndromology · 2023Article
- Long-read sequencing revealing intragenic deletions in exome-negative spastic paraplegias.Journal of human genetics · 2023Article
- Exome sequencing in a Romanian Bardet-Biedl syndrome cohort revealed an overabundance of causal BBS12 variants.American journal of medical genetics. Part A · 2023Article
- Rad52's DNA annealing activity drives template switching associated with restarted DNA replication.Nature communications · 2022Article
- Multi-pathway DNA-repair reporters reveal competition between end-joining, single-strand annealing and homologous recombination at Cas9-induced DNA double-strand breaks.Nature communications · 2022Article
- SVA Retrotransposons and a Low Copy Repeat in Humans and Great Apes: A Mobile Connection.Molecular biology and evolution · 2022Article
- A guide for the diagnosis of rare and undiagnosed disease: beyond the exome.Genome medicine · 2022Review
- Therapeutic Strategies for MutantBrain sciences · 2021Review
- A novel homozygous SLC13A5 whole-gene deletion generated by Alu/Alu-mediated rearrangement in an Iraqi family with epileptic encephalopathy.American journal of medical genetics. Part A · 2021Article
- Transposable elements, circular RNAs and mitochondrial transcription in age-related genomic regulation.Development (Cambridge, England) · 2020Review
11 more citing papers are in PubMed but not listed here.
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Authors and funding
23 authors at 12 institutions in 4 countries.
Funding
Abstract
Intragenic copy-number variants (CNVs) contribute to the allelic spectrum of both Mendelian and complex disorders. Although pathogenic deletions and duplications in SPAST (mutations in which cause autosomal-dominant spastic paraplegia 4 [SPG4]) have been described, their origins and molecular consequences remain obscure. We mapped breakpoint junctions of 54 SPAST CNVs at nucleotide resolution. Diverse combinations of exons are deleted or duplicated, highlighting the importance of particular exons for spastin function. Of the 54 CNVs, 38 (70%) appear to be mediated by an Alu-based mechanism, suggesting that the Alu-rich genomic architecture of SPAST renders this locus susceptible to various genome rearrangements. Analysis of breakpoint Alus further informs a model of Alu-mediated CNV formation characterized by small CNV size and potential involvement of mechanisms other than homologous recombination. Twelve deletions (22%) overlap part of SPAST and a portion of a nearby, directly oriented gene, predicting novel chimeric genes in these subjects' genomes. cDNA from a subject with a SPAST final exon deletion contained multiple SPAST:SLC30A6 fusion transcripts, indicating that SPAST CNVs can have transcriptional effects beyond the gene itself. SLC30A6 has been implicated in Alzheimer disease, so these fusion gene data could explain a report of spastic paraplegia and dementia cosegregating in a family with deletion of the final exon of SPAST. Our findings provide evidence that the Alu genomic architecture of SPAST predisposes to diverse CNV alleles with distinct transcriptional--and possibly phenotypic--consequences. Moreover, we provide further mechanistic insights into Alu-mediated copy-number change that are extendable to other loci.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.