title: Familial mutation in the testis-determining gene SRY shared by an XY female and her normal father.
abstract: In humans, mutations in the testis-determining gene SRY result in XY sex reversal with pure gonadal dysgenesis (PGD). However, only about 10-15% of the cases of PGD can be explained by mutations within the SRY open reading frame, suggesting the existence of other sex-determining genes. Although SRY is known to bind and bend DNA, its target and mode of action remain elusive. Here, we describe a novel mutation in SRY at codon 127, resulting in a tyrosine (Y) to phenylalanine (F) substitution in the protein. This sequence variant was found not only in the XY female patient but also in her father, who is a phenotypically normal male. However, this Y127F variant was not found in the SRY sequences of 93 other randomly chosen males. This substitution affects a highly conserved tyrosine residue in the HMG box of SRY, in which two de novo mutations have been described previously in XY females with PGD. Furthermore, electromobility shift studies demonstrate that SRY protein harboring the Y127F variant is incapable of binding consensus SRY binding sites in vitro. Taken together, these data suggest that the Y127F variant is a novel mutation with functional consequences and not simply a polymorphism. The allelic variant of SRY transmitted in this family and shared by both a phenotypic female (proband) and a phenotypic male (proband's father) emphasizes the importance of modifier genes in the sex determination pathway.
authors.affiliation: Department of Human Genetics, University of California at Los Angeles, 6954 Charles E. Young Drive South, Gonda Center, Los Angeles, CA 90095-7088, USA.
authors.forename: Brian K
authors.initials: BK
authors.lastname: Jordan
authors.forename: Manas
authors.initials: M
authors.lastname: Jain
authors.forename: Sathima
authors.initials: S
authors.lastname: Natarajan
authors.forename: S Douglas
authors.initials: SD
authors.lastname: Frasier
authors.forename: Eric
authors.initials: E
authors.lastname: Vilain
mesh_terms: D019943:Amino Acid Substitution; D001483:Base Sequence / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D005220:Fathers; D005260:Female; D024282:Genes, sry / Q000235:genetics*; D006061:Gonadal Dysgenesis, 46,XY / Q000235:genetics* / Q000473:pathology; D024742:HMG-Box Domains / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics; D009687:Nuclear Proteins; D010649:Phenylalanine; D016133:Polymerase Chain Reaction; D012016:Reference Values; D051876:Sex-Determining Region Y Protein; D013737:Testis / Q000502:physiology*; D014157:Transcription Factors; D014443:Tyrosine
chemical_list: D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors; D014443:Tyrosine; D010649:Phenylalanine