New York - An international team of researchers has found out why the DiGeorge syndrome often causes malformations of the kidneys. According to report in the New England Journal of Medicine (), the cause lies in mutations in the CRKL gene, protein that is important for kidney development.
One in 2,000 to 4,000 children is born with DiGeorge syndrome. It is sometimes referred to as CATCH-22 syndrome because of the predominant malformations of the heart (C for Cardiax), the "abnormal" face shape (A), thymus aplasia (T), jaw brace (C for cleft) and hypocalcemia with hypoparathyroidism (H). The “22” refers to the microdiletion in chromosome 22q11, which is responsible for the malformations.
Microdiletion leads to the loss of around 2.5 million base pairs, on which there are more than 40 genes. Research is currently underway to determine which genes are responsible for the individual malformations. In recent years it has been recognized that the cardiac malformations are due to the loss of the TBX1 gene. Now team led by Simone Sanna-Cherchi from Columbia University Medical Center has tracked down the cause of the kidney malformations that are present in around 30 percent of patients.
The researchers first carried out rough gene comparison of 2,666 children with malformations of the genitourinary system and 22,094 controls without malformations. 14 children with gene variants in chromosome 22q11 were discovered. They were on the section that is missing from DiGeorge Syndrome. A closer analysis was able to narrow down the responsible gene to range of nine genes.
The researchers have now used zebrafish to investigate the effects that the loss of individual genes has on kidney development. This allowed the search to be limited to three genes. These three genes have now been precisely sequenced in 586 children with malformations of the kidneys and genitourinary system. From the sequence of the bases, the researchers were able to deduce which of the gene variants is likely to lead to the formation of an altered and thus functionally defective protein. A defect was found in the CRKL gene.
The CRKL gene contains the information for an adapter protein that has an important role in the signaling of growth factors. One of these growth factors is the fibroblast growth factor. According to Sanna-Cherchi, disorder at this point explains in biologically plausible manner why developmental disorders of the kidneys occur. The final proof was provided by studies in mice in which the failure of the CRKL gene regularly led to malformations.