title: 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.
  
  
  METHODS
  Phenotypic, mutational, and functional study.
  
  
  METHODS
  Academic research unit.
  
  
  METHODS
  Two half-sisters, their common father, and 100 healthy control individuals.
  
  
  METHODS
  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.
  
  
  METHODS
  Not applicable.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Research Group Human Genetics, Division of Medical Genetics, Department of Biomedicine and University Children's Hospital, Basel, Switzerland. Isabel.Filges@unibas.ch
authors.forename: Isabel
authors.initials: I
authors.lastname: Filges
authors.forename: Christophe
authors.initials: C
authors.lastname: Kunz
authors.forename: Peter
authors.initials: P
authors.lastname: Miny
authors.forename: Nemya
authors.initials: N
authors.lastname: Boesch
authors.forename: Gabor
authors.initials: G
authors.lastname: Szinnai
authors.forename: Friedel
authors.initials: F
authors.lastname: Wenzel
authors.forename: Sibil
authors.initials: S
authors.lastname: Tschudin
authors.forename: Urs
authors.initials: U
authors.lastname: Zumsteg
authors.forename: Karl
authors.initials: K
authors.lastname: Heinimann
mesh_terms: D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D004247:DNA / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D024282:Genes, sry / Q000235:genetics*; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000378:metabolism; D024742:HMG-Box Domains / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009030:Mosaicism; D020125:Mutation, Missense / Q000235:genetics*; D011247:Pregnancy; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; D004247:DNA