A study of splicing mutations in disorders of sex development
A study of splicing mutations in disorders of sex development
The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation. Minigenes were used to validate the functional effect of mutations in both genes. We evaluated the c.277 + 2 T > G mutation in HSD17B3, and the c.544 G > A, c.548-44 T > G and c.278delG mutations in SRD5A2. We demonstrated that these mutations altered the splicing pattern of these genes. In a genomic era these results illustrate, and remind us, that sequence variants within exon-intron boundaries, which are primarily identified for diagnostic purposes and have unknown pathogenicity, need to be assessed with regards to their impact not only on protein expression, but also on mRNA splicing.
De Calais, Flavia Leme
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Smith, Lindsay D.
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Raponi, Michela
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Maciel-guerra, Andréa Trevas
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Guerra-junior, Gil
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De Mello, Maricilda Palandi
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Baralle, Diana
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24 November 2017
De Calais, Flavia Leme
d648d35b-dc15-426d-b62c-5e2367248bd9
Smith, Lindsay D.
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Raponi, Michela
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Maciel-guerra, Andréa Trevas
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Guerra-junior, Gil
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De Mello, Maricilda Palandi
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Baralle, Diana
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De Calais, Flavia Leme, Smith, Lindsay D., Raponi, Michela, Maciel-guerra, Andréa Trevas, Guerra-junior, Gil, De Mello, Maricilda Palandi and Baralle, Diana
(2017)
A study of splicing mutations in disorders of sex development.
Scientific Reports, 7 (1), [16202].
(doi:10.1038/s41598-017-16296-3).
Abstract
The presence of splicing sequence variants in genes responsible for sex development in humans may compromise correct biosynthesis of proteins involved in the normal development of gonads and external genitalia. In a cohort of Brazilian patients, we identified mutations in HSD17B3 and SRD5A2 which are both required for human sexual differentiation. A number of these mutations occurred within regions potentially critical for splicing regulation. Minigenes were used to validate the functional effect of mutations in both genes. We evaluated the c.277 + 2 T > G mutation in HSD17B3, and the c.544 G > A, c.548-44 T > G and c.278delG mutations in SRD5A2. We demonstrated that these mutations altered the splicing pattern of these genes. In a genomic era these results illustrate, and remind us, that sequence variants within exon-intron boundaries, which are primarily identified for diagnostic purposes and have unknown pathogenicity, need to be assessed with regards to their impact not only on protein expression, but also on mRNA splicing.
Text
SplicingDSD.2017
- Accepted Manuscript
More information
Accepted/In Press date: 10 November 2017
e-pub ahead of print date: 24 November 2017
Published date: 24 November 2017
Identifiers
Local EPrints ID: 415798
URI: http://eprints.soton.ac.uk/id/eprint/415798
ISSN: 2045-2322
PURE UUID: 3c56591d-3707-47cf-8c8f-9e68dee25523
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Date deposited: 24 Nov 2017 17:30
Last modified: 16 Mar 2024 03:57
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Contributors
Author:
Flavia Leme De Calais
Author:
Lindsay D. Smith
Author:
Michela Raponi
Author:
Andréa Trevas Maciel-guerra
Author:
Gil Guerra-junior
Author:
Maricilda Palandi De Mello
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