The Role of <i>SRY</i> Mutations in the Etiology of Gonadal Dysgenesis in Patients with 45,X/46,XY Disorder of Sex Development and Variants

Abstract

Background: The potential involvement of SRY in abnormal gonadal development in 45,X/46,X,der(Y) patients was proposed following the identification of SRY mutations in a few patients with Turner syndrome (TS). However, its exact etiological role in gonadal dysgenesis in patients with Y chromosome mosaicisms has not yet been clarified. Aims: It was the aim of this study to screen for allelic variation in SRY in a large cohort of patients with disorders of sex development due to chromosomal abnormalities with 45,X/46,X,der(Y) karyotype. Patients: Twenty-seven patients, 14 with TS and 13 with mixed gonadal dysgenesis (MGD), harboring 45,X/46,X,der(Y) karyotypes were selected. Methods: Genomic DNA was extracted from peripheral blood leukocytes of all patients and from gonadal tissue in 4 cases. The SRY coding region was PCR amplified and sequenced. Results: We identified only 1 polymorphism (c.561C→T) in a 45,X/46,XY MGD patient, which was detected in blood and in gonadal tissue. Conclusion: Our results indicate that mutations in SRY are rare findings in patients with Y chromosome mosaicisms. Therefore, a significant role of mutated SRY in the etiology of gonadal dysgenesis in patients harboring 45,X/46,XY karyotype and variants seems very unlikely.

SRY mutation analysis by next generation (deep) sequencing in a cohort of chromosomal Disorders of Sex Development (DSD) patients with a mosaic karyotype

“…The study by Cools et al [6] revealed no clear correlation between peripheral blood karyotype and gonadal karyotype, or between the gonadal karyotype and differentiation pattern found in the gonads. The inconsistency between gonadal karyotype and gonadal differentiation pattern cannot be explained by the presence of SRY mutations, as they are found only in rare cases, and do not seem to correlate with the differentiation pattern reported [11,12,14,21,23], even when ascertained by a highly sensitive next generation sequencing approach, as shown in this study.…”

“…The results presented here are in agreement with, and extend the data reported by (and others summarized in) Nishi et al . [14], who found only one SRY polymorphism (c.561C → T) in a group of 27 patients (fourteen TS and thirteen mixed gonadal dysgenesis patients. In Table 1, next to the cases analyzed here, an overview of SRY mutations that have been reported in chromosomal DSD cases is shown.…”

“…Most of the mutations detected are located in the HMG domain, responsible for the binding and bending of DNA, but several mutations outside of this domain have been reported. Several reports have also described mutations in the SRY gene in individuals with a 45,X/46,XY karyotype [11-14], suggesting an additional effect of mutant SRY in the gonadal development of these patients.…”

FISH and array CGH characterization of de novo derivative Y chromosome (Yq duplication and partial Yp deletion) in an azoospermic male

“…The short stature homeobox-containing gene ( SHOX ), encoding a transcription factor implicated in human growth, represents the single known disease gene within the PAR1 (band Yp11.32-p11.31) (Figure 2C) (Bernasconi and Garavelli, 2010). The SRY gene is mapped in band Yp11.31 but downstream to PAR1 sequences (Figure 2C) (Kadandale et al, 2000; Nishi et al, 2011). In turn, FISH analysis using mBAND probes revealed the duplication of most of Yq arm and that the duplicated region of Yq was translocated to the distal end of Yp (Figure 2H).…”

Current Concepts in Disorders of Sexual Development

“…1)Sex chromosome DSDs (45,X Turner and variants, 47,XXY Klinefelter and variants, 45X/46XY MGD, choromosomal ovotesticular DSD (46XX/46XY chimeric type or mosaic type): This type of DSDs is associated with a numerical sex chromosome abnormality leading to abnormal gonadal development (2,3,5,30,31,32,33,34, 35,36,37). Sex chromosome DSD was formerly termed as gonadal dysgenesis in most of the patients in this group (5).…”