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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
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
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
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.; Phenotypic, mutational, and functional study.; Academic research unit.; Two half-sisters, their common father, and 100 healthy control individuals.; 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.; Not applicable.; 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.; 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.