A novel missense mutation in the high mobility group domain of SRY drastically reduces its DNA-binding capacity and causes paternally transmitted 46,XY complete gonadal dysgenesis.

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.

• 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)
• Copyright: Copyright © 2011 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Chemical References

• DNA-Binding Proteins
• DNA

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