Baylor College of Medicine researchers recently published a study in Nature Medicine outlining the discovery of two types of birth defects found in newborn boys caused by a micro duplication on the X chromosome.
During the study, the team was able to identify the cause of the defect by analyzing a group of children who were born with testicular and penile development defects, which were a result of a mutation in the number of copies of the VAMP7 gene.
“The birth defects were a result of microduplication on the X chromosome that altered estrogen receptor and androgen receptor action in ways not previously recognized,” explained Dr. Dolores Lamb, director of the Center for Reproductive Medicine at BCM, professor and vice chair for research of urology and molecular and cellular biology at Baylor, and lead author of the report.
“Cryptorchidism and hypospadias are among the most common birth defects but the causes are usually unknown,” said Lamb. Cryptorchidism is an abnormality characterized by the failure of one or both testicles’ descent into the scrotum during fetal development, and occurs in about 3 percent of full term male births. Hypospadias are the result of an incorrect placement of the cavity of the urethra in the penis and affects about 1 in 125 births. Both conditions are usually surgically treated during the first years of life.
In the study, Lamb and her team used a method of genome wide screening called array, and the data was compared to genomic hybridization to study the defects. The scholars were specifically searching for transmutations in chromosomal regions that experienced duplication or an erasure of the number of gene copies. The genomic changes can alter the gene dosage, causing changes in the cells function.
The researchers also found a correlation between androgen and estrogen that work to regulate the differentiation of the male reproductive system. Androgen, such as testosterone, is a steroid hormone that stimulates or controls the development of male features, while estrogen is the primary female sex hormone. The reproductive system relies on the balance between them.
The results showed 1.35 percent of the 324 patients suffered gene duplication. “This is far more common than androgen receptor mutations or defects in other known genes affecting testicular descent during development, such as INSL3,” said Lamb. The duplication thesis was then tested and validated with mouse models of the human genomic duplication.
Understanding the VAMP7 gene duplication role provoking the defects also advance the knowledge about the entire system overall, since it belongs to a family of protein called Soluble N-ethylmaleimide-sensitive factor activating protein receptor (SNARE), which is a large protein superfamily with more than 60 members of both yeast and mammalian cells. Researchers believe these findings can improve diagnosis and treatment.
“This SNARE protein traffics the movement of other proteins in the cell. No one had ever considered that a minor change in the amount of this protein could so profoundly impact the estrogen receptor and to a lesser extent androgen receptor action resulting in these male reproductive birth defects,” she added.