Characterization of Alu and recombination-associated motifs mediating a large homozygous SPG7 gene rearrangement causing hereditary spastic paraplegia.
Spastic paraplegia type 7 (SPG7) is one of the most common forms of autosomal recessive hereditary spastic paraplegia (AR-HSP). Although over 77 different mutations have been identified in SPG7 patients, only 9 gross deletions have been reported with only a few of them being fully characterized. Here, we present a detailed description of a large homozygous intragenic SPG7 gene rearrangement involving a 5144-base pair (bp) genomic loss (c. 1450-446_1779 + 746 delinsAAAGTGCT) encompassing exons 11 to 13, identified in a Spanish AR-HSP family. Analysis of the deletion junction sequences revealed that the 5' breakpoint of this SPG7 gene deletion was located within highly homologous Alu sequences where the 3' breakpoint appears to be flanked by the core crossover hotspot instigator (chi)-like sequence (GCTGG). Furthermore, an 8-bp (AAAGTTGCT) conserved sequence at the breakpoint junction was identified, suggesting that the most likely mechanism for the occurrence of this rearrangement is by Alu microhomology and chi-like recombination-associated motif-mediated multiple exon deletion. Our results are consistent with non-allelic homologous recombination and non-homologous end joining in deletion mutagenesis for the generation of rearrangements. This study provides more evidence associating repeated elements as a genetic mechanism underlying neurodegenerative disorders, highlighting their importance in human diseases.
Centre de Diagnòstic Genètic i Molecular (CDGM)-Institut de Recerca Biomèdica de Bellvitge (IDIBELL), Gran Via 199, 08907, L'Hospitalet de Llobregat, Barcelona, Spain, etoledano@idibell.cat.
Eva
E
López
Carlos
C
Casasnovas
Javier
J
Giménez
Antoni
A
Matilla-Dueñas
Ivelisse
I
Sánchez
Víctor
V
Volpini
D000074183:ATPases Associated with Diverse Cellular Activities; D000368:Aged; D020087:Alu Elements; D005260:Female; D015321:Gene Rearrangement; D006720:Homozygote; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics*; D009154:Mutation; D010264:Paraplegia / Q000235:genetics; D010375:Pedigree; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics
D008666:Metalloendopeptidases; C112889:SPG7 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities