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A study of splicing mutations in disorders of sex development

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.
2045-2322
De Calais, Flavia Leme
d648d35b-dc15-426d-b62c-5e2367248bd9
Smith, Lindsay D.
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Raponi, Michela
f465e77f-b9bf-4c32-80d6-43c0787542b9
Maciel-guerra, Andréa Trevas
f8523992-8d39-4dc1-8866-0591e88fab8a
Guerra-junior, Gil
fdd8251f-dd13-4985-ab71-8ed517746f6f
De Mello, Maricilda Palandi
66daea67-45b5-4afa-9e4b-ef81f8cd010e
Baralle, Diana
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De Calais, Flavia Leme
d648d35b-dc15-426d-b62c-5e2367248bd9
Smith, Lindsay D.
1d44c2d0-d5af-411e-b6cd-9b5633f2eb1e
Raponi, Michela
f465e77f-b9bf-4c32-80d6-43c0787542b9
Maciel-guerra, Andréa Trevas
f8523992-8d39-4dc1-8866-0591e88fab8a
Guerra-junior, Gil
fdd8251f-dd13-4985-ab71-8ed517746f6f
De Mello, Maricilda Palandi
66daea67-45b5-4afa-9e4b-ef81f8cd010e
Baralle, Diana
faac16e5-7928-4801-9811-8b3a9ea4bb91

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).

Record type: Article

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.

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SplicingDSD.2017 - Accepted Manuscript
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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
ORCID for Diana Baralle: ORCID iD orcid.org/0000-0003-3217-4833

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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
Author: Diana Baralle ORCID iD

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