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

作者：Filges Isabel^*; Kunz Christophe; Miny Peter; Boesch Nemya; Szinnai Gabor; Wenzel Friedel; Tschudin Sibil; Zumsteg Urs; Heinimann Karl

来源：Fertility and Sterility, 2011, 96(4): 851-U299.

DOI：10.1016/j.fertnstert.2011.07.1137

• Swyer syndrome
• 46,XY complete gonadal dysgenesis
• SRY
• gonadal mosaicism
• HMG domain
• c.347T &gt
• C

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. (Fertil Steril (R) 2011;96:851-5.

• 出版日期2011-10