Y Chromosome Mutation Can Lead To Sex Reversal and Cancer

Michael A. Weiss, MD, PhD The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor andMedicalResearch.com Interview with:
Michael A. Weiss, MD, PhD

The Cowan-Blum Professor and Chairman of the Department of Biochemistry Distinguished Research Professor and Professor of Medicine in the Endocrine Division at the Case Western Reserve School of Medicine in Cleveland, Ohio.

Joseph Racca Researcher and graduate student Department of BiochemistryJoseph Racca
Researcher and graduate student
Department of Biochemistry

Case Western Reserve School of Medicine in Cleveland, Ohio.

Medical Research: What is the background for this study? What are the main findings?

Response: The function of the gene responsible for male differentiation, sex-determining region of the Y chromosome (SRY), was first demonstrated in transgenic mouse models by P. Koopman, R. Lovell-Badge and colleagues in the early 1990s. These findings were corroborated by identification of mutations in human SRY that are associated with human sex reversal: XY, 46 gonadal dysgenesis leading to somatic sex reversal (Swyer’s Syndrome). Such mutations may occur spontaneously in spermatogenesis or be inherited. The characterization of the molecular defects associated with these mutations has unmasked novel biological and biochemical activities of SRY. More broadly, such studies have also increased our understanding of an entire family of related transcription factors (Sry-box related; SOX), which broadly function in metazoan development (from worms, fish and flies to mammals). Within human SRY, the majority of clinical mutations occur in the region of the protein responsible for specific DNA binding and DNA bending, the primary molecular actions of SRY at target genes. Our study bridges structure (i.e., protein folding and stability) and function (i.e., transcriptional activation of target genes and related cell-biological processes such as trafficking and proteosomal degradation).

In our current study, we highlighted the importance of a structural scaffold in human SRY, specifically a key single amino acid that buttresses the unique L-shape structure of this domain. The mutation of interest represents a “perfect storm” leading to deleterious effects on multiple activities, including specific DNA binding, cellular localization, and both protein and cellular stability (lifetime), among other properties, together leading to sex reversal and cancer (gonadoblastoma) in the proband patient. Our integrated multi-disciplinary approach allowed us to characterize these various facets of SRY in the context of its biological site of action: the pre-Sertoli cell in an embryonic gonadal ridge just prior to its morphological differentiation into a testis. We are grateful to Prof. Patricia K. Donahoe (Harvard Medical School and the Massachusetts General Hospital), who generously provided this micro-dissected pre-Sertoli cell line.

Medical Research: What should clinicians and patients take away from your report?

Response: Mutations in SRY associated with sex reversal may coincide with the formation of gonadoblastoma, pediatric malignancy containing a solid mass of undifferentiated cells types.

Although patients harboring mutations in SRY may exhibit a continuum of phenotypes, all XY sex-reversed females are sterile. The XY gonads are intra-abdominal, scarred and prone to cancer. On microscopic examination, such gonads lack differentiated features of either testes or ovaries. In childhood, such patients will otherwise grow normally as girls. At the onset of puberty, however, the XY child will not begin to have periods (“primary amenorrhea”); pubic hair and breast development is typically within the normal range.

An important aspect of this study is the use of an integrated approach to probe the molecular functions of SRY. Due to the location of this mutation (within the DNA-binding domain), it might have been annotated as simply a DNA binding defect. Such a domain-based annotation would have missed the “perfect storm” of perturbations to the cellular biochemistry of the protein and general biophysical importance of the general aromatic-buttress motif in the overall SOX family of transcription factors. Our integrated and multi-disciplinary approach revealed multiple facets of structure and function. The editors of The Journal of Biological Chemistry highlighted this study as a “Paper of the Week” in light of such beautiful facets: the findings highlight the utility of clinical mutations as key “experiment of nature” to probe the subtle inter-relation of structure, function and phenotype that underlies developmental gene regulation.

Medical Research: What recommendations do you have for future research as a result of this study?

Response: As previously mentioned, this location of this mutation is within the DNA binding and bending region of human SRY and this region also harbors the majority of sex reversal mutations. What this particular mutation taught was that these mutations are “nature-designed” probes for structure-functions studies. Furthermore, we have undertaken studies of inherited mutations to study how subtle defects in SRY can lead to two different developmental outcomes. Our ongoing studies of candidate SRY mutations are providing molecular insights into mechanistic details of how this protein functions as a switch in development. Also, our over-arching general concepts will (with regard to specific DNA binding and bending and conserved cellular functions), as we believe, relate to the entire family of related transcription factors.


Joseph D. Racca, Yen-Shan Chen, James D. Maloy, Nalinda Wickramasinghe, Nelson B. Phillips, and Michael A. Weiss
Biol. Chem. 2014 289: 32410-32429. First Published on September 24, 2014, doi:10.1074/jbc.M114.597526


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