A Novel Frame Shift Mutation in the HMG Box of the SRY Gene in a Patient With Complete 46,XY Pure Gonadal Dysgenesis

Abstract

Pure gonadal dysgenesis or Swyer syndrome is a sex-reversal disorder resulting from embryonic testicular regression sequences especially during the first few weeks of fetal life and is induced by mutations in the SRY gene. In the present report, we describe a nonmosaic XY sex-reversed female with pure gonadal dysgenesis. Molecular analysis using sequential PCR to detect Y chromosomal microdeletions showed the presence of SRY, ZFY and AZFa, b and c regions. Automated sequencing of the SRY region revealed a new mutation (deletion of A (adenine) in codon 82 at position +244), leading to a frame shift mutation within the helix I of the HMG-box domain. This mutation generates a truncated protein and is very likely to produce an impairment of SRY DNA binding activity. The present findings further support the functional importance of the putative DNA binding activity of the SRY HMG-box domain.

Identification of a new mutation in the SRY gene in a 46,XY woman with Swyer syndrome

“…In fact, the debate on whether SRY mutations are related to cancer development in Swyer syndrome is still open: Kellermayer et al (9) and Iliopoulos et al (13) seem to suggest the strong cause-effect relation between SRY mutations and tumor development, although there is no clear scientific evidence. In fact, mutated SRY is suspected to promote cancer genesis but is not the only cause.…”

“…In fact, mutated SRY is suspected to promote cancer genesis but is not the only cause. Kellermayer et al (9) and Uehara et al (12) underlined the role of other age-related cancer genes in gonadoblastoma and dysgerminoma development. It remains unclear whether SRY could act as a tumor suppressor gene or an oncogene.…”

“…The SRY sequence analysis disclosed a new single nucleotide insertion at codon 13 position 38, 38-39insA, leading to a truncated SRY protein. This is the third frameshift mutation in the SRY gene, the ninth at the 5 0 region upstream the HMG box (9)(10)(11).…”

Species Identification and Sex Determination of Korean Water Deer (Hydropotes inermis argyropus) by Duplex PCR

“…A transcription regulatory motif of HMG was contained in the amino acid sequence of SRY, which is commonly found in the SRY and its related proteins and plays a key role in regulating the gene expression required for transcriptional activation and testis development (Li et al, 2006;Phillips et al, 2006). Mutations in this region are reported to be associated with XY pure gonadal dysgenesis as well as sex-reversal disorders (Kellermayer et al, 2005;Gimelli et al, 2007). However, mutations compared to that of the other cervids in the HMG region of water deer (Fig 2) were not associated with critical function of SRY protein because there was no sexual disorder in water deer based on their phenotypes recorded in specimenproviders.…”

Global gene profiling and comprehensive bioinformatics analysis of a 46,XY female with pericentric inversion of the Y chromosome

“…SRY (the sex-determining region of the Y chromosome; GenBank accession number NM_003140), a testis-determining gene (Sinclair et al 1990;Koopman et al 1991), is located on the short arm of the Y chromosome and plays a critical role in initiating testis formation during gonadal development (Koopman et al 1990(Koopman et al , 1991. However, the mode of SRY action is poorly understood, even though 19 years have passed since the SRY gene was identified in 1990, and the presence of missense mutation (Hawkins et al 1992a;Zeng et al 1993;Imai et al 1999;Okuhara et al 2000;Shahid et al 2004), nonsense mutation (Müller et al 1992;Hawkins et al 1992a;Iida et al 1994;Giuffrè et al 2004), or frame shift mutation (Jäger et al 1990;Kellermayer et al 2005) in the SRY gene has been detected in only approximately 10-20% of XY females (Hawkins et al 1992b;Lim et al 1998). Therefore, the cause of DSD has been highly controversial.…”