title: Identification of a new missense mutation (Gly95Glu) in a highly conserved codon within the high-mobility group box of the sex-determining region Y gene: report on a 46,XY female with gonadal dysgenesis and yolk-sac tumor.
abstract: Leydig cells and Sertoli cells of the testes produce hormones that cause male differentiation, if receptors are present. The Y chromosomal SRY gene (sex determining Region Y gene) acts as TDF and is required for regular male sex determination. SRY represents a transcription factor belonging to the superfamily of genes sharing the HMG-box motif(high-mobility group-box), which acts as DNA binding region. Here, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis (46,XY karyotype, completely female external genitalia, normal Müllerian ducts, absence of Wolffian ducts, streak gonads) who harbored a yolk-sac tumor and was referred for the assessment of primary amenorrhea. Using genomic PCR analysis, a 423-bp PCR product, encompassing the HMG-box of the SRY gene, was amplified from the proposita, her father, and her three brothers, whereas no band was visible in the patient's mother and her three sisters. The PCR products were sequenced for mutations subsequently. A new de novo missense mutation within the HMG-box of the SRY gene was discovered in the proposita. A G is replaced by an A in codon 95 at position +284, resulting in the replacement of the nonpolar aminoacid glycine by the polar amino acid glutamate. The glycine at codon 95 is highly conserved between the family of HMG-box proteins and between species. This point mutation has not been described earlier and brings the total number of SRY mutations described so far to 36, each mutation being unique. This mutation was not detected in the patient's father and her male siblings. The present data provide further evidence to support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.
authors.affiliation: Department of Internal Medicine I, University of Regensburg, Germany. andreas.schaeffler@klinik.uni-regensburg.de
authors.forename: A
authors.initials: A
authors.lastname: Schäffler
authors.forename: N
authors.initials: N
authors.lastname: Barth
authors.forename: K
authors.initials: K
authors.lastname: Winkler
authors.forename: B
authors.initials: B
authors.lastname: Zietz
authors.forename: P
authors.initials: P
authors.lastname: Rümmele
authors.forename: R
authors.initials: R
authors.lastname: Knüchel
authors.forename: J
authors.initials: J
authors.lastname: Schölmerich
authors.forename: K D
authors.initials: KD
authors.lastname: Palitzsch
mesh_terms: D000328:Adult; D000595:Amino Acid Sequence; D003062:Codon; D017124:Conserved Sequence; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics*; D018240:Endodermal Sinus Tumor / Q000235:genetics* / Q000473:pathology; D005260:Female; D018698:Glutamic Acid; D005998:Glycine; D006059:Gonadal Dysgenesis / Q000235:genetics* / Q000473:pathology; D006801:Humans; D007621:Karyotyping; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D009687:Nuclear Proteins; D010641:Phenotype; D017433:Protein Structure, Secondary; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D019849:Sex Determination Processes; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors; D014960:X Chromosome; D014998:Y Chromosome
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C497745:SRY protein, human; D051876:Sex-Determining Region Y Protein; D014157:Transcription Factors; D018698:Glutamic Acid; D005998:Glycine