Document Detail


Alu-specific microhomology-mediated deletion of the final exon of SPAST in three unrelated subjects with hereditary spastic paraplegia.
MedLine Citation:
PMID:  21659953     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Autosomal 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.
METHODS: We 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.
RESULTS: We 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.
CONCLUSION: We 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.
Authors:
Philip M Boone; Pengfei Liu; Feng Zhang; Claudia M B Carvalho; Charles F Towne; Sat Dev Batish; James R Lupski
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural    
Journal Detail:
Title:  Genetics in medicine : official journal of the American College of Medical Genetics     Volume:  13     ISSN:  1530-0366     ISO Abbreviation:  Genet. Med.     Publication Date:  2011 Jun 
Date Detail:
Created Date:  2011-06-10     Completed Date:  2011-09-28     Revised Date:  2013-12-12    
Medline Journal Info:
Nlm Unique ID:  9815831     Medline TA:  Genet Med     Country:  United States    
Other Details:
Languages:  eng     Pagination:  582-92     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Adenosine Triphosphatases / genetics*
Alu Elements / genetics*
Alzheimer Disease / genetics
Base Sequence
Cation Transport Proteins / genetics
Exons
Gene Expression
Humans
Introns
Molecular Sequence Data
Sequence Analysis, DNA
Sequence Deletion
Spastic Paraplegia, Hereditary / genetics*
Grant Support
ID/Acronym/Agency:
M01 RR000188/RR/NCRR NIH HHS; R01 NS058529/NS/NINDS NIH HHS; R01NS058529/NS/NINDS NIH HHS; T32 EY007102/EY/NEI NIH HHS; T32GM007330-34/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Cation Transport Proteins; 0/SLC30A6 protein, human; EC 3.6.1.-/Adenosine Triphosphatases; EC 3.6.1.-/SPAST protein, human
Comments/Corrections

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