So far, it is being reported as a recessive cause for fertility, meaning that two mutations, one from each parent, are required for the disease to present itself. We found a family case that we found to have a homozygous variant in DMC1 and reached out to several collaborating groups to identify additional cases with DMC1 variants. Despite this gene importance, there were surprisingly few cases previously reported and within our own search that had variants in this gene.
For our study, we explored the volume of literature to get an understanding of how our observed variants may cause disease, using family segregation, computational effect prediction, and 3D modeling to better understand how the mutations affect the function. In our cases, we found the mutations may have changed how two DMC1 proteins interact with each other. In our search, we found that while a complete loss of the DMC1 gene is generally recessive in eukaryotes, certain point mutations displayed a stronger, dominant effect. It does not appear consistent, and that only certain key positions would have such a strong impact across several eukaryotes. Given this consistency, we believed that it was likely we could observe a similar relationship in humans. We found one possible candidate, as it likely affects a position that has a modeled dominant variant.
Written by: Noor Ullah,1 Christopher Pombar,2 Rachel Hvasta-Gloria,2 Andrea J. Berman,3 Michelle Malizio,2 Muhammad Jaseem Khan,1 Rubina Nazli,1 Sadia Fatima,1 Antoni Riera-Escamilla,4 Helen Castillo-Madeen,4 Agnieszka Malcher,5 Marta Olszewska,5 Miguel J. Xavier,6 Kristiina Lillepea,7 Avirup Dutta,7 Carlos A. Castro,2 Anu Valkna,7 Rain Inno,7 Kyle E. Orwig,2 Donald F. Conrad,4 Maciej Kurpisz,5 Joris A. Veltman,6 Maris Laan,7 Alexander N. Yatsenko2,8,9
- Department of Biochemistry, Institute of Basic Medical Sciences, Khyber Medical University, Peshawar, Pakistan.
- Department of Obstetrics, Gynecology, and Reproductive Sciences, Magee-Womens Research Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
- Department of Biological Sciences, Dietrich School of Arts and Sciences, University of Pittsburgh, Pittsburgh, USA.
- Department of Genetics, Oregon National Primate Research Center, Oregon Health and Science University, Beaverton, OR, USA.
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
- Faculty of Medical Sciences, Biosciences Institute, Newcastle University, Newcastle Upon Tyne, UK.
- Genetics, Institute of Biomedicine and Translational Medicine, University of Tartu, Tartu, Estonia.
- Department of Pathology, School of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
- Department of Genetics, School of Public Health, University of Pittsburgh, Pittsburgh, PA, USA.