TY - JOUR
T1 - Characterization of Alu and recombination-associated motifs mediating a large homozygous SPG7 gene rearrangement causing hereditary spastic paraplegia
AU - López, Eva
AU - Casasnovas, Carlos
AU - Giménez, Javier
AU - Matilla-Dueñas, Antoni
AU - Sánchez, Ivelisse
AU - Volpini, Víctor
PY - 2015/3/18
Y1 - 2015/3/18
N2 - © 2014, Springer-Verlag Berlin Heidelberg. 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.
AB - © 2014, Springer-Verlag Berlin Heidelberg. 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.
KW - Alu-mediated non-allelic homologous recombination
KW - Chi-like recombination-associated motif
KW - Hereditary spastic paraplegia
KW - Large gene rearrangement
KW - Paraplegin
KW - SPG7
U2 - 10.1007/s10048-014-0429-6
DO - 10.1007/s10048-014-0429-6
M3 - Article
VL - 16
SP - 97
EP - 105
JO - Neurogenetics
JF - Neurogenetics
SN - 1364-6745
IS - 2
ER -