English
 
User Manual Privacy Policy Disclaimer Contact us
  Advanced SearchBrowse

Item

ITEM ACTIONSEXPORT
  Pathogenic abnormal splicing due to intronic deletions that induce biophysical space constraint for spliceosome assembly.

Bryen, S. J., Joshi, H., Evesson, F. J., Girard, C., Ghaoui, R., Waddell, L. B., et al. (2019). Pathogenic abnormal splicing due to intronic deletions that induce biophysical space constraint for spliceosome assembly. American Journal of Human Genetics, 105(3), 573-587. doi:10.1016/j.ajhg.2019.07.013.

Item is

Basic

show hide
Item Permalink: http://hdl.handle.net/21.11116/0000-0004-972A-3 Version Permalink: http://hdl.handle.net/21.11116/0000-0004-A0E5-4
Genre: Journal Article

Files

show Files

Locators

show

Creators

show
hide
 Creators:
Bryen, S. J., Author
Joshi, H., Author
Evesson, F. J., Author
Girard, C., Author
Ghaoui, R., Author
Waddell, L. B., Author
Testa, A. C., Author
Cummings, B., Author
Arbuckle, S., Author
Graf, N., Author
Webster, R., Author
MacArthur, D. G., Author
Laing, N. G., Author
MR, Davis, Author
Lührmann, R.1, Author              
Cooper, S. T., Author
Affiliations:
1Department of Cellular Biochemistry, MPI for biophysical chemistry, Max Planck Society, ou_578576              

Content

show
hide
Free keywords: 5′ splice site; abnormal splicing; branchpoint; intronic deletion; non-coding variant; pathogenic splice variant; pre-mRNA splicing; spliceosome assembly
 Abstract: A precise genetic diagnosis is the single most important step for families with genetic disorders to enable personalized and preventative medicine. In addition to genetic variants in coding regions (exons) that can change a protein sequence, abnormal pre-mRNA splicing can be devastating for the encoded protein, inducing a frameshift or in-frame deletion/insertion of multiple residues. Non-coding variants that disrupt splicing are extremely challenging to identify. Stemming from an initial clinical discovery in two index Australian families, we define 25 families with genetic disorders caused by a class of pathogenic non-coding splice variant due to intronic deletions. These pathogenic intronic deletions spare all consensus splice motifs, though they critically shorten the minimal distance between the 5' splice-site (5'SS) and branchpoint. The mechanistic basis for abnormal splicing is due to biophysical constraint precluding U1/U2 spliceosome assembly, which stalls in A-complexes (that bridge the 5'SS and branchpoint). Substitution of deleted nucleotides with non-specific sequences restores spliceosome assembly and normal splicing, arguing against loss of an intronic element as the primary causal basis. Incremental lengthening of 5'SS-branchpoint length in our index EMD case subject defines 45-47 nt as the critical elongation enabling (inefficient) spliceosome assembly for EMD intron 5. The 5'SS-branchpoint space constraint mechanism, not currently factored by genomic informatics pipelines, is relevant to diagnosis and precision medicine across the breadth of Mendelian disorders and cancer genomics.

Details

show
hide
Language(s): eng - English
 Dates: 2019-08-22
 Publication Status: Published online
 Pages: -
 Publishing info: -
 Table of Contents: -
 Rev. Method: Peer
 Identifiers: DOI: 10.1016/j.ajhg.2019.07.013
 Degree: -

Event

show

Legal Case

show

Project information

show

Source 1

show
hide
Title: American Journal of Human Genetics
Source Genre: Journal
 Creator(s):
Affiliations:
Publ. Info: -
Pages: - Volume / Issue: 105 (3) Sequence Number: - Start / End Page: 573 - 587 Identifier: -