TY - JOUR
T1 - The alu-rich genomic architecture of SPAST predisposes to diverse and functionally distinct disease-associated CNV alleles
AU - Boone, Philip M.
AU - Yuan, Bo
AU - Campbell, Ian M.
AU - Scull, Jennifer C.
AU - Withers, Marjorie A.
AU - Baggett, Brett C.
AU - Beck, Christine R.
AU - Shaw, Christine J.
AU - Stankiewicz, Pawel
AU - Moretti, Paolo
AU - Goodwin, Wendy E.
AU - Hein, Nichole
AU - Fink, John K.
AU - Seong, Moon Woo
AU - Seo, Soo Hyun
AU - Park, Sung Sup
AU - Karbassi, Izabela D.
AU - Batish, Sat Dev
AU - Ordóñez-Ugalde, Andrés
AU - Quintáns, Beatriz
AU - Sobrido, María Jesús
AU - Stemmler, Susanne
AU - Lupski, James R.
N1 - Funding Information:
The authors thank the Spastic Paraplegia Foundation, Sandy Wilcock, and Amy Breman for assistance with subject/sample recruitment. We thank Gladys Zapata and Paula Patricia Hernandez for transforming lymphoblasts and Chad Shaw, Claudia Fonseca, and Avinash Dharmadhikari for technical advice. We are grateful to the Spanish Familial Spastic Paraplegia Association (AEPEF) and the European Hereditary Spastic Paraplegia Federation (Euro-HSP) for their support and collaboration. P.M.B. and I.M.C. are fellows of the Baylor College of Medicine Medical Scientist Training Program (T32GM007330). P.M.B. is supported by grants from the Wintermann Foundation and the Baylor Research Advocates for Student Scientists. I.M.C. was supported by a fellowship from the National Institute of Neurological Disorders and Stroke (F31 NS083159). C.R.B. is an HHMI Fellow of the Damon Runyon Cancer Research Foundation (DRG 2155-13). This work was supported in part by the US National Institute of Neurological Disorders and Stroke (RO1NS058529 to J.R.L.), the US National Human Genome Research Institute/National Heart, Blood and Lung Institute (U54HG006542), and the Spanish Fondo de Investigaciones Sanitarias (PS09/01830). J.K.F. is supported by the Spastic Paraplegia Foundation, the U.S. National Institute of Neurological Disorders and Stroke (RO1NS0679700), the U.S. Department of Veterans Affairs (Merit Review 5I01CX000344), the Geriatric Research Education and Clinical Center AAVAMC, and the Paul and Lois Katzman Family. J.R.L. holds stock ownership in 23andMe, Inc. and Ion Torrent Systems, Inc., and is a coinventor on multiple United States and European patents related to molecular diagnostics. M.J.S. is a shareholder of Genomic Consulting, a company related to the application of genomics in medicine. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered in the Medical Genetics Laboratories. I.D.K. and S.D.B. are employees of Quest Diagnostics.
PY - 2014/8/7
Y1 - 2014/8/7
N2 - 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.
AB - 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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U2 - 10.1016/j.ajhg.2014.06.014
DO - 10.1016/j.ajhg.2014.06.014
M3 - Article
C2 - 25065914
AN - SCOPUS:84905900217
SN - 0002-9297
VL - 95
SP - 143
EP - 161
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
IS - 2
ER -