Two common birth defects among boys around the world may now be explained genetically, scientists reported Sunday in the journal Nature Medicine.
"Cryptorchidism and hypospadias are among the most common birth defects but the causes are usually unknown," Dolores Lamb, director of the Center for Reproductive Medicine at Baylor College, said in a press statement.
Cryptochidism is the more common and less serious of the two birth defects, striking three percent of newborn boys. The defect may effect later fertility as one or both testes in the scrotum fail to descend during fetal development from the body cavity, though the condition often reverses itself during childhood.
More rarely, hypospadias strikes one in 125 newborn boys with the abnormal placement of the opening of the urethra on the penis, a condition that may be reversed with surgery.
The researchers employed the new technique of genome-wide screening called comparative genomic hybridization to discover the genetic roots of the two defects. They searched for changes in chromosomal regions following duplication or deletions too small to be seen by microscope. Such genomic changes may result in the altering of cellular function, producing birth defects.
Those two common defects were shown to be the result of changes in the number of copies of the VAMP7 gene. Of 324 patients in the study, the gene duplication occurred in 1.35 percent but was not present at all in nearly 9,000 others in a control group.
"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," Lamb said. The interbalance between androgen and estrogen in differentiating the male reproductive system during fetal development is a delicate one, he added.
The link between the gene duplication and the two birth defects to the male reproductive tract was also verified using a mouse study modeled after the human genome study, with the same birth defects occuring in the mouse model. The implicated gene also interests the researchers as part of a larger type of proteins called SNARE, or Soluble N-ethylmaleimide-sensitive factor activating protein receptor.
"This SNARE protein traffics the movement of other proteins in the cell,” Lamb said. “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."
At the very least, the researchers say the findings will help to improve diagnoses, with hope for improved treatments in the future.
Source: Lamb D, Tannour-Louet M, Han S, et al. Increased gene copy number of VAMP7 disrupts human male urogenital development through altered estrogen action. Nature Medicine. 2014.