Abstract | OBJECTIVE: To investigate the familial segregation, role, and function of a novel SRY missense mutation c.347T>C in two half-sisters affected by 46,XY complete gonadal dysgenesis (CDG) compatible with a successful pregnancy outcome. DESIGN: Phenotypic, mutational, and functional study. SETTING: Academic research unit. PATIENT(S): Two half-sisters, their common father, and 100 healthy control individuals. INTERVENTION(S): Chromosome, molecular cytogenetic analysis, and Sanger sequencing of the SRY gene in blood lymphocytes of the proband, her affected half-sister, and in inflammatory tissue of the father postmortem. Cloning and expression of high mobility group box carboxy-terminal domains of Sry and electrophoretic mobility shift assay were performed. MAIN OUTCOME MEASURE(S): Not applicable. RESULT(S): A novel SRY missense mutation c.347T>C (p.Leu116Ser) was identified in two half-sisters and segregates with the CGD phenotype. It is present in the common healthy father in a mosaic state. Functional analyses demonstrate the pathogenic effect of the mutation by a strong reduction of DNA affinity for the mutant p.Leu116Ser SRY protein. CONCLUSION(S): The missense mutation c.347T>C in the high mobility group domain of SRY causes 46,XY CGD. Paternal gonadal mosaicism is likely to explain the familial occurrence of 46,XY CGD suggesting a de novo mutational event during the early stages of embryonic development. This novel mutation is compatible with a successful pregnancy outcome.
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Authors | Isabel Filges, Christophe Kunz, Peter Miny, Nemya Boesch, Gabor Szinnai, Friedel Wenzel, Sibil Tschudin, Urs Zumsteg, Karl Heinimann |
Journal | Fertility and sterility
(Fertil Steril)
Vol. 96
Issue 4
Pg. 851-5
(Oct 2011)
ISSN: 1556-5653 [Electronic] United States |
PMID | 21868002
(Publication Type: Comparative Study, Journal Article)
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Copyright | Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved. |
Chemical References |
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Topics |
- Adolescent
- Adult
- Amino Acid Sequence
- DNA
(genetics, metabolism)
- DNA-Binding Proteins
(genetics, metabolism)
- Female
- Genes, sry
(genetics)
- Gonadal Dysgenesis, 46,XY
(genetics, metabolism)
- HMG-Box Domains
(genetics)
- Humans
- Male
- Middle Aged
- Molecular Sequence Data
- Mosaicism
- Mutation, Missense
(genetics)
- Pregnancy
- Young Adult
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