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A key gene contributes to common birth defects

Human chromosome 22 is a hotspot for a variety of birth defects. Scientists learned about the 22q11.2 region of chromosome 22 because it is deleted in about 1 in 4,000 births, causing loss or duplication in up to 40 genes. Chromosome micro-deletion or micro-duplication can result in a number of developmental abnormalities which can vary greatly in severity.


What many of the genes do in the 22q11.2 region is not well understood, but when a set of these genes is absent we can see havoc in the development and function of the heart, immune system and craniofacial features, as well as issues in cognition and behavior. About 30 percent of individuals with a condition, called DiGeorge syndrome or 22q11.2 deletion syndrome, may also have developmental abnormalities in their genitourinary system, with both upper- and lower-tract defects.

Congenital (present from birth) genitourinary birth defects, whether as part of a syndrome such as DiGeorge syndrome or as isolated congenital abnormalities, are among the most common types of birth defects. Cryptorchidism, or undescended testis, occurs in about 6 percent of full-term male births, and hypospadias, a defect in which the opening of the urethra is not located at the tip of the penis, is seen in 1 in 250 male births. Defining the causes of genitourinary birth defects has been a focus of research in Dr. Dolores Lamb's laboratory for many years.

The work is published in the Proceedings of the National Academy of Sciences PNAS.


""About 12 years ago, we began studying genitourinary birth defects with a technique called array comparative genomic hybridization … essentially … at very high resolution so we can see little gains or losses in regions of chromosomes. We studied a number of unrelated children with cryptorchidism or hypospadias using this technology and found about 20 percent of them had micro-deletions or micro-duplications that clustered in specific regions of different chromosomes. One small deleted or duplicated chromosome region associated with these genitourinary conditions is 22q11.2. The children, however, were not diagnosed with DiGeorge syndrome."

Dolores J. Lamb PhD, Department of Molecular & Cellular Biology, and Department of Urology, Baylor College of Medicine, Houston, Texas, USA and corresponding author for the study.


Researchers found that the changes were 'de novo,' or new in the children, meaning they were not present in the parents. Lamb and colleagues set out to identify which genes in 22q11.2 are most likely involved in the abnormal development of the genitourinary system. If these genes were identified and their functions understood, researchers could then develop diagnostic tools and potential treatments for individuals affected by this condition.

Finding genes involved in developmental disorders is like finding the missing or altered pieces in a complex, broken machine for which we don't have the blue print. Scientists use several strategies to find gene candidates and test their functions in the lab.

Their analysis, together with creative thinking about potential pathways impacted by a gene dosage change, led the team to suspect a gene called CRKL was the most likely candidate at 22q11.2 to be involved in genitourinary abnormalities as a result of gene duplication or deletion. Further analysis showed that in humans, CRKL is expressed in a variety of fetal tissues, including liver, lung, skeletal muscle, as well as in the heart, spleen, thymus, brain and kidney, all relevant to DiGeorge syndrome. In the mouse and human, CRKL is expressed modestly throughout development, including in the developing genitourinary tract. These results led the researchers to their next step toward determining CRKL's involvement in genitourinary defects.

They genetically engineered mice to lack CRKL. One group of mice lacked both copies of the gene, one received from the mother and the one passed on by the father, while another group lacked only one of the two CRKL copies. Lacking both copies of the gene was lethal for any embryo, highlighting the importance of CRKL in embryonic development.

Analysis of both groups of embryos showed intrauterine growth restriction. In addition to having neural, heart and other congenital defects, about 23 percent of the mice exhibited severe kidney abnormalities. Like the human patients, male mice lacking one copy of CRKL had failure of testicular descent into the scrotum (cryptorchidism) resulting in fewer-than-average number of pups per litter, and with aging this sub-fertility progressed to male infertility. Further analysis showed that crkl regulates genitourinary development by altering expression of at least 52 DNA transcripts.


"Our data show that having CRKL gene dosage changes in this region, including the loss of one copy of CRKL, can negatively affect normal genitourinary (specifically testicular descent) and kidney development. CRKL has partial penetrance, so we see that some patients are affected while others aren't. There is a spectrum of severity between different individuals; this inter-individual variation was also present in the mouse model."

Dolores J. Lamb PhD


Significance
Common deletions affecting multiple genes that cause multiple birth defects can be studied by investigating each gene’s independent role in embryonic development. This study shows that a specific gene, CRKL, which lies within the commonly deleted region at chromosome locus 22q11.2, is required for normal overall embryonic growth, and normal development of the kidneys and testes. Deletion of only the Crkl gene in mice is sufficient to cause increased incidence of birth defects commonly seen in humans who possess deletion at 22q11.2. This study shows that CRKL is one of the key genes whose deletion contributes to the urogenital birth defects associated with multiple-gene deletion at chromosome 22q11.2, indicating a new target for gene therapy in affected patients.

Abstract
The spectrum of congenital anomalies affecting either the upper tract (kidneys and ureters) or lower tract (reproductive organs) of the genitourinary (GU) system are fundamentally linked by the developmental origin of multiple GU tissues, including the kidneys, gonads, and reproductive ductal systems: the intermediate mesoderm. Although ~31% of DiGeorge/del22q11.2 syndrome patients exhibit GU defects, little focus has been placed on the molecular etiology of GU defects in this syndrome. Among del22q11.2 patients exhibiting GU anomalies, we have mapped the smallest relevant region to only five genes, including CRKL. CRKL encodes a src-homology adaptor protein implicated in mediating tyrosine kinase signaling, and is expressed in the developing GU-tract in mice and humans. Here we show that Crkl mutant embryos exhibit gene dosage-dependent growth restriction, and homozygous mutants exhibit upper GU defects at a microdissection-detectable rate of 23%. RNA-sequencing revealed that 52 genes are differentially regulated in response to uncoupling Crkl from its signaling pathways in the developing kidney, including a fivefold up-regulation of Foxd1, a known regulator of nephron progenitor differentiation. Additionally, Crkl heterozygous adult males exhibit cryptorchidism, lower testis weight, lower sperm count, and subfertility. Together, these data indicate that CRKL is intimately involved in normal development of both the upper and lower GU tracts, and disruption of CRKL contributes to the high incidence of GU defects associated with deletion at 22q11.2.

Other authors: Meade Haller, Qianxing Mo, Akira Imamoto

Keywords: del22q11.2 haploinsufficient genitourinary urogenital congenital defects




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Human Chromosome 22 and related traitsHuman Chromosome 22 and related traits
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