title: The Alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles.
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.
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Philip M
authors: PM
authors: Boone
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Bo
authors: B
authors: Yuan
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Ian M
authors: IM
authors: Campbell
authors: Medical Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Jennifer C
authors: JC
authors: Scull
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Marjorie A
authors: MA
authors: Withers
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Brett C
authors: BC
authors: Baggett
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Christine R
authors: CR
authors: Beck
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Christine J
authors: CJ
authors: Shaw
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Medical Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA.
authors: Pawel
authors: P
authors: Stankiewicz
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Department of Neurology, Baylor College of Medicine, Houston, TX 77030, USA; Michael E. DeBakey VA Medical Center, Houston, TX 77030, USA.
authors: Paolo
authors: P
authors: Moretti
authors: Children's Medical Center of Dallas, Dallas, TX 75207, USA.
authors: Wendy E
authors: WE
authors: Goodwin
authors: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA.
authors: Nichole
authors: N
authors: Hein
authors: Department of Neurology, University of Michigan, Ann Arbor, MI 48109, USA; Geriatrics Research Education and Clinical Center, Ann Arbor, MI 48105, USA; Veterans Affairs Medical Center, Ann Arbor, MI 48015, USA.
authors: John K
authors: JK
authors: Fink
authors: Department of Laboratory Medicine, Seoul National University Hospital, Seoul 110-799, Korea.
authors: Moon-Woo
authors: MW
authors: Seong
authors: Department of Laboratory Medicine, Seoul National University Hospital, Seoul 110-799, Korea.
authors: Soo Hyun
authors: SH
authors: Seo
authors: Department of Laboratory Medicine, Seoul National University Hospital, Seoul 110-799, Korea.
authors: Sung Sup
authors: SS
authors: Park
authors: Quest Diagnostics, Athena Diagnostics, Worcester, MA 01605, USA.
authors: Izabela D
authors: ID
authors: Karbassi
authors: Quest Diagnostics, Athena Diagnostics, Worcester, MA 01605, USA.
authors: Sat Dev
authors: SD
authors: Batish
authors: Fundación Pública Galega de Medicina Xenómica-SERGAS, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
authors: Andrés
authors: A
authors: Ordóñez-Ugalde
authors: Fundación Pública Galega de Medicina Xenómica-SERGAS, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
authors: Beatriz
authors: B
authors: Quintáns
authors: Fundación Pública Galega de Medicina Xenómica-SERGAS, IDIS, CIBERER, Santiago de Compostela 15706, Spain.
authors: María-Jesús
authors: MJ
authors: Sobrido
authors: Department of Human Genetics, Ruhr University, Bochum 44801, Germany.
authors: Susanne
authors: S
authors: Stemmler
authors: Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA; Medical Genetics Laboratories, Baylor College of Medicine, Houston, TX 77030, USA; Texas Children's Hospital, Houston, TX 77030, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, USA. Electronic address: jlupski@bcm.edu.
authors: James R
authors: JR
authors: Lupski
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D020087:Alu Elements / Q000235:genetics*; D001483:Base Sequence; D027682:Cation Transport Proteins / Q000235:genetics*; D002461:Cell Line, Transformed; D056915:DNA Copy Number Variations / Q000235:genetics*; D005838:Genotype; D006801:Humans; D020033:Protein Isoforms / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D017422:Sequence Analysis, DNA; D017384:Sequence Deletion; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics*; D000074181:Spastin
chemical_list: D027682:Cation Transport Proteins; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins; C504822:SLC30A6 protein, human; D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human