Understanding Hydatidiform Moles
Definition and Causes
A hydatidiform mole, commonly referred to as a molar pregnancy, is characterized by a human pregnancy that lacks a normally developing embryo. This condition typically arises when an egg contains two sets of paternal DNA and one set of maternal DNA. In cases of complete hydatidiform moles, the fertilized egg is believed to be devoid of maternal DNA, containing only paternal DNA from the sperm. Since maternal and paternal DNA play distinct roles in embryonic development, an egg lacking maternal DNA is unable to develop properly. However, the absence of reports on empty eggs suggests that an alternative process may be involved.
Prevalence and Treatment
Hydatidiform moles occur in approximately 1 in every 600 pregnancies, with the more common form not having a well-defined cause. Treatments for molar pregnancies typically involve dilation and curettage (D&C), a procedure that removes tissue from the uterus, or chemotherapy, depending on the specific type of mole. Generally, these procedures do not have long-term negative effects on fertility. Nevertheless, around 10% of women may experience recurrent hydatidiform moles, and between 17% to 37% of affected women may never achieve a live birth.
Recent Genetic Research
Study Overview
A recent study published in the *American Journal of Human Genetics* by Nguyen and colleagues from the McGill University Health Centre in Quebec, Canada, explores genetic mutations associated with recurrent hydatidiform moles. The researchers collected genetic samples from 65 women who had experienced recurrent molar pregnancies, miscarriages, and infertility, ruling out mutations in two previously identified genes, NLRP7 and KHDC3L.
Methodology
The collected samples underwent exome sequencing, which targets specific DNA regions that code for proteins. Additionally, 345 women with less severe conditions were screened for mutations in the genes identified in the original 65 samples. The impact of these mutations was subsequently tested in mice.
Key Findings
The study uncovered deleterious mutations in the MEI1, TOP6BL/C11orf80, and REC114 genes in five unrelated women from the original cohort. Notably, MEI1 mutations were identified in at least two unrelated women who had a history of multiple miscarriages and molar pregnancies, with similar fertility issues reported among their siblings. Importantly, women carrying these mutations exhibited a different mechanism for molar pregnancies compared to those with NLRP7 or KHDC3L mutations.
In murine models, the MEI1 mutation resulted in infertility, contingent upon the presence of two copies of the mutation. Males with this mutation produced no sperm, while females had abnormal eggs that degenerated rapidly. Eggs from females with the double MEI1 mutation displayed improper chromosomal distribution during cell division. Approximately 60% of these eggs were fertilized by multiple sperm or lacked evidence of maternal DNA. Although they could develop to the 2- or 4-cell stage, they were unlikely to implant normally. Additionally, REC114 was found to directly interact with MEI1.
Implications and Future Research
These findings provide valuable insights into the underlying causes of molar pregnancies and suggest that mutations in MEI1, TOP6BL, and REC114 may also contribute to miscarriage. Further research is necessary to better understand the connections between molar pregnancies and miscarriages, as well as to clarify the influence of genetic mutations in both conditions.
Reference
Nguyen et al. 2018. Causative mutations and mechanism of androgenetic hydatidiform moles. *Am J Hum Genet* 103:740-751.