Navigation Links
Scientists solve 30-year-old mystery of mutant mouse's kidney woes

Researchers seeking insights into kidney failure in human infants have located the source of a 30-year-old mystery mutation that causes similar problems in a mouse line.

Scientists have known of the mouse line's naturally occurring mutation since the early 1970s. Researchers at Washington University School of Medicine in St. Louis are the first to identify the mutated gene, allowing them to determine the mutation's effects and the origins of the disease.

"The gene codes for a protein that moves water across membranes, and we showed that the mutated form of the protein doesn't get properly distributed in the urinary system," says senior author Feng Chen, Ph.D., assistant professor of medicine. "If something similar happens in human disorders, one way to treat such diseases would be to redirect the protein to its appropriate location."

Results from Chen and his colleagues are published online in the Proceedings of the National Academy of Sciences.

Ultrasonic scans reveal fetal hydronephrosis, or enlargement of the kidney, in approximately 1 in every 100 human fetuses. The condition results from impairment of passage of urine from the kidney to the bladder. About 20 percent of those cases lead to clinical complications that, if left untreated, can include kidney failure and death.

Scientists suspect a variety of environmental and genetic factors contribute to fetal hydronephrosis. However, they frequently cannot tie it to any causative factors, making it difficult to determine how normal molecular and cellular processes in kidney development break down in infants affected by the condition.

Researchers at The Jackson Laboratory first noted the mouse line's mutation in the early 1970s when some of the mice developed enlarged bellies and died within three to four weeks of their birth. Scientists initially assumed that the mutation was causing a form of polycystic kidney disease, but a follow-up study more than a decade later showed that passage of urine from the kidney was blocked, and the condition was renamed congenital progressive hydronephrosis.

With assistance from the mouse genome sequence and Li Ding, Ph.D., a research instructor at the Genome Sequencing Center at Washington University, Chen and his colleagues showed that the protein mutated in the mice is aquaporin 2 (aqp2), which belongs to an important family of proteins that channel water across membranes.

"We knew that the aqp2 protein is found in the principal cells of the collecting duct, the final stretch of the kidney filtration machinery," Chen says. "Water and some other useful components are reabsorbed from the urine here. The concentrated urine is then passed on to the bladder and other downstream parts of the urinary system."

When scientists used an antibody to identify where aqp2 is in the kidneys of the mutant mice, they saw that distribution of the protein was changed. Normally aqp2 is concentrated on the side of collection duct cells that faces the urine, where aqp2 can extract water from the waste stream for recirculation in the body. In the mutant mice, though, aqp2 was scattered around the collection duct cells.

"The protein is still there, but it's not in the right place," Chen says. "To make sure this was the cause and not just a result of the problem, we analyzed the sequence of the aqp2 gene from the mutant mice, comparing it to the gene from other normal mice, and found a single base pair had changed."

The change swaps the amino acid serine for the amino acid leucine at a key position in the protein. Serine can undergo phosphorylation, a form of chemical modification frequently used in biological processes; leucine cannot. This change apparently disrupts the processes that otherwise produce a normal distribution pattern for the protein.

Chen compares the machinery that transfers water from the kidney to a plumbing system. With aqp2 unable to rea bsorb water, he says, that results in up to 30 times more urine being dumped into the downstream pipes.

"Eventually, you overwhelm the plumbing system, and it gets backed up to an upstream location: the kidney," Chen says.

Chen plans follow-up studies of aqp2 to determine how important various parts of the protein are to its proper distribution in the kidney collecting duct epithelium. His lab also is looking for other genetic factors that contribute to renal diseases.


'"/>

Source:Washington University School of Medicine


Related biology news :

1. Scientists ID molecular switch in liver that triggers harmful effects of saturated and trans fats
2. Scientists Replicate Hepatitis C Virus in Laboratory
3. Scientists detect probable genetic cause of some Parkinsons disease cases
4. Scientists find missing enzyme for tuberculosis iron scavenging pathway
5. Scientists seek answers on what activates deadly anthrax spores
6. Yale Scientists Find MicroRNA Regulates Ras Cancer Gene
7. Scientists collaborate to assess health of global environment
8. Scientists decipher genome of fungus that can cause life-threatening infections
9. Scientists discover the cellular roots of graying hair
10. Scientists rid stem cell culture of key animal cells
11. Scientists develop new color-coded test for protein folding
Post Your Comments:
*Name:
*Comment:
*Email:


(Date:4/13/2017)... UBM,s Advanced Design and Manufacturing event in ... and evolving technology through its 3D Printing and Smart ... the expo portion of the event and feature a ... on trending topics within 3D printing and smart manufacturing. ... will take place June 13-15, 2017 at the Jacob K. ...
(Date:4/11/2017)... 11, 2017 Crossmatch®, a globally-recognized leader ... today announced that it has been awarded a ... Activity (IARPA) to develop next-generation Presentation Attack Detection ... "Innovation has been a driving force within Crossmatch ... allow us to innovate and develop new technologies ...
(Date:4/11/2017)... 11, 2017 No two people are ... the New York University Tandon School of Engineering ... found that partial similarities between prints are common ... mobile phones and other electronic devices can be ... vulnerability lies in the fact that fingerprint-based authentication ...
Breaking Biology News(10 mins):
(Date:9/19/2017)... ... September 19, 2017 , ... ... for surgical applications, announced today that two new patents have been allowed by ... MD, Co-Founder of Band-LOK, said, “We continue to explore additional clinically-relevant designs for ...
(Date:9/18/2017)... ... September 18, 2017 , ... USDM Life Sciences ... the life sciences and healthcare industries, announces Bryan Coddington and ... Transformation in Medical Device – The Journey to FDA Compliant Field Service and ...
(Date:9/14/2017)... Philadelphia PA and London UK (PRWEB) , ... ... ... company, will gather the most innovative minds in pharma and biotech at the ... is a two-day collaborative conference that brings together the world’s most progressive clinical ...
(Date:9/14/2017)... Antonio, Texas (PRWEB) , ... September 14, 2017 , ... ... San Antonio on Saturday, Sept. 16. , For six hours that day, the GenCure ... Match registry at more than 30 H-E-B grocery stores in San Antonio. , The ...
Breaking Biology Technology: