Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing

Autoři: Israel Ben-Dor aff001;  Crystal Pacut aff002;  Yuval Nevo aff003;  Eva L. Feldman aff002;  Benjamin E. Reubinoff aff001
Působiště autorů: The Hadassah Human Embryonic Stem Cell Research Center, The Goldyne Savad Institute of Gene Therapy, Hadassah Medical Center, Jerusalem, Israel aff001;  Department of Neurology, University of Michigan Medical School, Ann Arbor, MI, United States of America aff002;  Computation Center, Hebrew University–Hadassah Medical School, Jerusalem, Israel aff003
Vyšlo v časopise: Characterization of C9orf72 haplotypes to evaluate the effects of normal and pathological variations on its expression and splicing. PLoS Genet 17(3): e1009445. doi:10.1371/journal.pgen.1009445
Kategorie: Research Article


Expansion of the hexanucleotide repeat (HR) in the first intron of the C9orf72 gene is the most common genetic cause of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) in Caucasians. All C9orf72-ALS/FTD patients share a common risk (R) haplotype. To study C9orf72 expression and splicing from the mutant R allele compared to the complementary normal allele in ALS/FTD patients, we initially created a detailed molecular map of the single nucleotide polymorphism (SNP) signature and the HR length of the various C9orf72 haplotypes in Caucasians. We leveraged this map to determine the allelic origin of transcripts per patient, and decipher the effects of pathological and normal HR lengths on C9orf72 expression and splicing. In C9orf72 ALS patients’ cells, the HR expanded allele, compared to non-R allele, was associated with decreased levels of a downstream initiated transcript variant and increased levels of transcripts initiated upstream of the HR. HR expanded R alleles correlated with high levels of unspliced intron 1 and activation of cryptic donor splice sites along intron 1. Retention of intron 1 was associated with sequential intron 2 retention. The SNP signature of C9orf72 haplotypes described here enables allele-specific analysis of transcriptional products and may pave the way to allele-specific therapeutic strategies.

Klíčová slova:

Alleles – Fibroblasts – Gene mapping – Haplotypes – Heterozygosity – Introns – Polymerase chain reaction – Single nucleotide polymorphisms


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