Research indicates that a significant percentage of babies with genitourinary (GU) defects have gene abnormalities in three key chromosomal regions associated with known syndromic conditions and would benefit from a visit to a medical geneticist, according to Dolores Lamb, PhD, HCLD (ABB), Vice Chair for Research in the Department of Urology and Director of the Center for Reproductive Genomics at Weill Cornell Medicine.
Dr. Lamb reviewed her research into the genetic causes of common upper and lower GU tract birth defects during the annual John Duckett Memorial Lecture on Sunday.
“It’s important to remember that these GU anomalies often come in groups,” she said. “They appear with other GU defects or other developmental problems, and this is because there was a common embryonic origin.”
To determine the molecular basis for these birth defects, Dr. Lamb and her research team tested the hypothesis that they could start with the babies themselves, do advanced genetic analysis, identify structural chromosomal defects and then identify single candidate genes. With that information, they could then develop mouse models to show causation.
“We used array comparative genomic hybridization, which we can think of as a molecular karyotype. This is an array-based technology,” explained Dr. Lamb, noting that the research team compared GU-abnormal patients to GU-normal controls to see gene dosage loss or gene dosage changes.
Dr. Lamb provided results from the three chromosomal regions studied: a microduplication at Xq28 on the long arm of the X and Y chromosomes, microdeletions at 22q11.2 on chromosome 22 and microdeletions at 16p11.2 on chromosome 16.
“We used in vivo models, specifically mouse models, to prove that the mice would have the same birth defect when they had the same defect seen in our babies,” Dr. Lamb said, adding that all the babies they studied were non-syndromic and had the GU birth defect hypospadias and/or cryptorchidism.
Dr. Lamb discussed the candidate genes the researchers identified in each of the three chromosomal regions studied. For the microduplication at Xp28, the researchers identified VAMP7 as the candidate gene.
“We could not understand how we were seeing what seemed to be a steroid receptor-mediated type defect causing the GU birth defects that we were seeing. But we let the data talk to us,” she said. “It turned out that when you had excess VAMP7 present in these patients, that we were essentially blunting the action of the androgen receptor potentiating the action of the estrogen receptor.”
In chromosomal region 22q11.2 the researchers identified the candidate gene CRKL. Dr. Lamb noted that region 22q11.2 is a well-known duplications and deletions syndrome region, and that deficiencies in the CRKL gene disrupt signaling of fibroblast growth factor 8.
“The gene [CRKL] is also the one that seems to copy at least the DiGeorge Syndrome neurodevelopmental and cardiac deficiencies seen in children. So we hypothesized that deficiency of this gene was also contributing to the GU birth defects seen in the patients,” Dr. Lamb said.
Using mouse models, the researchers were able to show that CRKL deletion resulted in an increased incidence of upper and lower tract GU defects, including unilateral renal agenesis in the embryos.
“We could not look at the adults because when you delete the entire gene, it’s embryonic lethal,” she said.
When they deleted one copy of the CRKL gene, it resulted in cryptorchidism, smaller testes, and an age-related decline in fertility and fecundity because of a plummeting sperm count as the mice aged.
The researchers identified chromosomal region 16p11.2 as another hotspot for key genes that regulate GU development and are involved in congenital GU anomalies. They identified candidate gene MAZ and found that MAZ copy variations were more likely in patients with GU abnormalities.
“When we knocked out this gene in our mouse models, we saw that they had congenital anomalies of the kidney and urinary tract,” said Dr. Lamb, adding that MAZ-deficient mice also exhibited other GU, cardiac and ocular defects.