A study of splicing mutations in disorders of sex development

Author(s)

de Calais, Flavia Leme ^{[1, 2]} ; Smith, Lindsay D. ^{[2, 3]} ; Raponi, Michela ^[2] ; Maciel-Guerra, Andrea Trevas ^[4] ; Guerra-Junior, Gil ^[5] ; de Mello, Maricilda Palandi ^[1] ; Baralle, Diana ^{[2, 6]}

Affiliation

^[1] Univ Estadual Campinas, Ctr Biol Mol & Engn Genet, Campinas, SP - Brazil

^[2] Univ Southampton, Fac Med, Human Dev & Hlth, Southampton, Hants - England

^[3] Univ Southampton, Fac Med, Canc Sci Unit, Southampton, Hants - England

^[4] Univ Estadual Campinas, Dept Genet, Fac Ciencias Med, Campinas, SP - Brazil

^[5] Univ Estadual Campinas, Dept Pediat, Fac Ciencias Med, Campinas, SP - Brazil

^[6] Southampton Univ Hosp NHS Trust, Wessex Clin Genet Serv, Southampton, Hants - England

• Document type: Journal article
• Source: SCIENTIFIC REPORTS; v. 7, NOV 24 2017.
• Web of Science Citations: 1

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. (AU)