Disease-causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE-2 and antisense Alu lacking the poly(T)-tail
Disease-causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE-2 and antisense Alu lacking the poly(T)-tail
Cryptic exons or pseudoexons are typically activated by point mutations that create GT or AG dinucleotides of new 5 or 3 splice sites in introns, often in repetitive elements. Here we describe two cases of tetrahydrobiopterin deficiency caused by mutations improving the branch point sequence and polypyrimidine tracts of repeat-containing pseudoexons in the PTS gene. In the first case, we demonstrate a novel pathway of antisense Alu exonization, resulting from an intronic deletion that removed the poly(T)-tail of antisense AluSq. The deletion brought a favorable branch point sequence within proximity of the pseudoexon 3 splice site and removed an upstream AG dinucleotide required for the 3 splice site repression on normal alleles. New Alu exons can thus arise in the absence of poly(T)-tails that facilitated inclusion of most transposed elements in mRNAs by serving as polypyrimidine tracts, highlighting extraordinary flexibility of Alu repeats in shaping intron-exon structure. In the other case, a PTS pseudoexon was activated by an A>T substitution 9 nt upstream of its 3 splice site in a LINE-2 sequence, providing the first example of a disease-causing exonization of the most ancient interspersed repeat. These observations expand the spectrum of mutational mechanisms that introduce repetitive sequences in mature transcripts and illustrate the importance of intronic mutations in alternative splicing and phenotypic variability of hereditary disorders
RNA, mutation, long interspersed nuclear element, Alu, hyperphenylalaninemia, tetrahydrobiopterin, PTS
823-831
Meili, David
b085da32-6718-4258-bcd3-dbefea898266
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Zagalak, Julian
0d8f4efb-a7b1-422a-b264-78b0f5ea671f
Bonafe, Luisa
76ca6b90-d84d-4826-8407-1cee992e3514
Fiori, Laura
75b290df-73c4-47da-ba69-ede53444c99e
Blau, Nenad
279da193-1d00-4b9c-a427-d9df60b11de3
Thony, Beat
be069bee-1037-4294-b4b7-b3536a882107
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
May 2009
Meili, David
b085da32-6718-4258-bcd3-dbefea898266
Kralovicova, Jana
b3e0c1e7-05ed-445d-b3d9-ace11e3b4878
Zagalak, Julian
0d8f4efb-a7b1-422a-b264-78b0f5ea671f
Bonafe, Luisa
76ca6b90-d84d-4826-8407-1cee992e3514
Fiori, Laura
75b290df-73c4-47da-ba69-ede53444c99e
Blau, Nenad
279da193-1d00-4b9c-a427-d9df60b11de3
Thony, Beat
be069bee-1037-4294-b4b7-b3536a882107
Vorechovsky, Igor
7245de2f-8c9b-4034-8935-9a451d9b682e
Meili, David, Kralovicova, Jana, Zagalak, Julian, Bonafe, Luisa, Fiori, Laura, Blau, Nenad, Thony, Beat and Vorechovsky, Igor
(2009)
Disease-causing mutations improving the branch site and polypyrimidine tract: pseudoexon activation of LINE-2 and antisense Alu lacking the poly(T)-tail.
Human Mutation, 30 (5), .
(doi:10.1002/humu.20969).
Abstract
Cryptic exons or pseudoexons are typically activated by point mutations that create GT or AG dinucleotides of new 5 or 3 splice sites in introns, often in repetitive elements. Here we describe two cases of tetrahydrobiopterin deficiency caused by mutations improving the branch point sequence and polypyrimidine tracts of repeat-containing pseudoexons in the PTS gene. In the first case, we demonstrate a novel pathway of antisense Alu exonization, resulting from an intronic deletion that removed the poly(T)-tail of antisense AluSq. The deletion brought a favorable branch point sequence within proximity of the pseudoexon 3 splice site and removed an upstream AG dinucleotide required for the 3 splice site repression on normal alleles. New Alu exons can thus arise in the absence of poly(T)-tails that facilitated inclusion of most transposed elements in mRNAs by serving as polypyrimidine tracts, highlighting extraordinary flexibility of Alu repeats in shaping intron-exon structure. In the other case, a PTS pseudoexon was activated by an A>T substitution 9 nt upstream of its 3 splice site in a LINE-2 sequence, providing the first example of a disease-causing exonization of the most ancient interspersed repeat. These observations expand the spectrum of mutational mechanisms that introduce repetitive sequences in mature transcripts and illustrate the importance of intronic mutations in alternative splicing and phenotypic variability of hereditary disorders
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Published date: May 2009
Keywords:
RNA, mutation, long interspersed nuclear element, Alu, hyperphenylalaninemia, tetrahydrobiopterin, PTS
Organisations:
Human Genetics
Identifiers
Local EPrints ID: 69681
URI: http://eprints.soton.ac.uk/id/eprint/69681
ISSN: 1059-7794
PURE UUID: 4f38a168-3ee3-4a9b-b77b-c957a44dd21d
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Date deposited: 26 Nov 2009
Last modified: 14 Mar 2024 02:48
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Contributors
Author:
David Meili
Author:
Jana Kralovicova
Author:
Julian Zagalak
Author:
Luisa Bonafe
Author:
Laura Fiori
Author:
Nenad Blau
Author:
Beat Thony
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