ArticleGenetics in medicine : official journal of the American College of Medical Genetics2011
Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia.
Article in Genetics in medicine : official journal of the American College of Medical Genetics, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 41 papers.
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41 citing papers in PubMed, 56 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
- Identification of a novel non-coding deletion in Allan-Herndon-Dudley syndrome by long-read HiFi genome sequencing.BMC medical genomics · 2025Article
- Article
- Copy Number Variations in Hereditary Spastic Paraplegia-Related Genes: Evaluation of an Iranian Hereditary Spastic Paraplegia Cohort and Literature Review.Molecular syndromology · 2023Article
- Rad52's DNA annealing activity drives template switching associated with restarted DNA replication.Nature communications · 2022Article
- Transposable element-mediated rearrangements are prevalent in human genomes.Nature communications · 2022Article
- Biallelic Variants in the Ectonucleotidase ENTPD1 Cause a Complex Neurodevelopmental Disorder with Intellectual Disability, Distinct White Matter Abnormalities, and Spastic Paraplegia.Annals of neurology · 2022Article
- De novo heterozygous variants in SLC30A7 are a candidate cause for Joubert syndrome.American journal of medical genetics. Part A · 2022Article
- Hereditary Spastic Paraplegia: An Update.International journal of molecular sciences · 2022Review
- Distinct patterns of complex rearrangements and a mutational signature of microhomeology are frequently observed in PLP1 copy number gain structural variants.Genome medicine · 2019Article
- Genetic and Clinical Profile of Chinese Patients with Autosomal Dominant Spastic Paraplegia.Molecular diagnosis & therapy · 2019Article
- 2018 Victor A. McKusick Leadership Award: Molecular Mechanisms for Genomic and Chromosomal Rearrangements.American journal of human genetics · 2019Article
- Breakpoint junction features of seven DMD deletion mutations.Human genome variation · 2019Article
- Replicative and non-replicative mechanisms in the formation of clustered CNVs are indicated by whole genome characterization.PLoS genetics · 2018Article
- Predicting human genes susceptible to genomic instability associated withGenome research · 2018Article
- Retrotransposon-induced mosaicism in the neural genome.Open biology · 2018Review
- Mapping the genomic landscape of inherited retinal disease genes prioritizes genes prone to coding and noncoding copy-number variations.Genetics in medicine : official journal of the American College of Medical Genetics · 2018Article
- WNT Signaling Perturbations Underlie the Genetic Heterogeneity of Robinow Syndrome.American journal of human genetics · 2018Article
- RNA Editing and Retrotransposons in Neurology.Frontiers in molecular neuroscience · 2018Review
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Authors and funding
7 authors at 3 institutions in 2 countries.
Funding
Abstract
purposeAutosomal dominant spastic paraplegia, type 4 (SPG4), a debilitating disorder of progressive spasticity and weakness of the lower limbs, results from heterozygous mutations in the SPAST gene. The full spectrum of SPAST mutations causing SPG4 and their mechanisms of formation remain to be determined.
methodsWe used multiplex ligation-dependent probe amplification, locus-specific array comparative genomic hybridization, and breakpoint DNA sequencing to identify and describe genomic rearrangements in three patients with a clinical presentation of hereditary spastic paraplegia.
resultsWe describe three SPG4 patients with intragenic rearrangements in SPAST; all specifically delete the final exon, exon 17. Breakpoint sequence analyses provide evidence for Alu-specific microhomology-mediated deletion as the mechanism of exon loss; one complex rearrangement apparently occurred by multiple Alu-facilitated template switches.
conclusionWe hypothesize that the high concentration of Alu family members in the introns and flanking sequence of SPAST may predispose to intragenic rearrangements. Thus, Alu-specific microhomology-mediated intragenic rearrangements in SPAST may be a common cause of SPG4. Furthermore, we propose that genomic deletions encompassing the final exon of SPAST may affect expression of SLC30A6, the most proximal downstream locus and a gene that has been implicated in the pathogenesis of Alzheimer disease, potentially explaining recent reports of dementia in selected SPG4 patients.
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