Editor's note: Science Scan is a roundup of recently published biotechnology-relevant research.
The most frequent genetic cause of end-stage kidney failure in children and young adults is a renal disorder called nephronophthisis (NPHP). Its pathomechanism has been obscure for decades. Four genetic loci underlying NPHP had previously been mapped, but with only two genes sequenced so far, nephrocystin and nephrocystin-4. Both are linked to a chronic infantile form of NHPH (on the long arm of chromosome 9).
The August 2003 issue of Nature Genetics reports that a form of NHPH found in infants is caused by mutations in a gene called inversin (INVS). The paper is titled "Mutations in INVS encoding inversin cause nephronophthisis type 2, which links renal cystic disease to the function of primary cilia and left-right axis determination."
Its authors are research pediatricians at the University of Michigan in Ann Arbor. They report that a form of NPHP found in babies is caused by mutations in the inversin gene, and confirmed this connection in a zebrafish model of the disease. This animal model, the paper noted, "produced a PKD-like renal cystic phenotype and randomization of heart looping by knockdown of INVS expression." The authors also found that inversin interacts with nephrocystin, and occurs in the kidney's primary cilium. Those cilia affect the portion of the kidney that is affected in polycystic kidney disease, which has overlapping features with NPHP.
Their paper shows that nephrocystin, inversin and btubulin (a main component of primary cilia) co-localize to primary cilia of renal tubular cells. The co-authors analyzed 16 exons of INVS in genomic DNA from nine affected individuals in seven families, including one individual and affected siblings from the Bedouin kindred in which the NPHP2 locus first was mapped.
A second article in the same Nature Genetics bears the title "Mutations in a novel gene, NPHP3, cause adolescent nephronophthisis, tapeto-retinal degeneration and hepatic fibrosis." It encodes a 1,330-amino-acid protein that interacts with nephrocystin.
The authors show that mutations in NPHP3 likely are the cause of the polycystic kidneys seen in a mouse model called pcy. They propose that "NPHP may be associated with Leber congenital amaurosis, tapeto-retinal degeneration, cerebellar ataxia, cone-shaped epiphyses (part of a long bone), congenital ocular apraxia and hepatic fibrosis."
"Interventional studies in the pcy mouse," the paper concludes, "have shown beneficial effects by modification of protein intake and administration of methylprednisolone [an anti-inflammatory corticosteroid], suggesting therapeutic strategies for treating individuals with NPHP3."
Life-Or-Death Angioplasty Prediction Tested In 1,458 Dutch Patients With C-Reactive Protein
Predicting possible complications in coronary-care patients who are about to undergo angioplasty can benefit both the patient and the cardiologist. A report published in the August 2003 issue of The American Journal of Medicine carries the title, "C-reactive protein and coronary events following percutaneous coronary angioplasty."
Its co-authors examined whether increased levels of C-reactive protein (CRP) in patients undergoing percutaneous angioplasty are linked to further complications or death. In this study, 1,458 consecutive patients at the University of Amsterdam in the Netherlands participated. They measured blood levels of CRP at the beginning of the impending procedure. Follow-up questionnaires and interviews completed the investigation.
The article noted, "Mortality was significantly greater in patients with an increased C-reactive protein level, as was the incidence of nonfatal myocardial infarction. In fact, the relative risk of death or infarction was more than four times as high in patients with high CRP levels. In contrast, an abnormal CRP level was not associated with repeat revascularization."
An accompanying editorial commented, "The clinical utility of these indicators will depend on the ability to measure their levels in serum or plasma accurately and reliably, and on their predictive value as demonstrated in clinical studies. This marker appears not to be a reliable predictor of restenosis per se, but rather a strong consistent predictor of native coronary artery disease-related events."
The co-authors concluded that "clinical studies incorporating anti-inflammatory treatment prior to percutaneous coronary intervention are awaited with great interest."
Anglo-Swiss Co-Authors Weigh Mating Activity Of Sex Peptide In Male, Female Fruit Flies
An ejaculatory protein known as the "sex peptide" (SP) may increase egg-laying and reduce sexual receptivity in female fruit flies, according to new data by two independent teams of researchers. One is at University College in Oxford, UK; the other, at the University of Zurich in Switzerland.
Their reports appear in the Proceedings of the National Academy of Science (PNAS), released July 22, 2003, under the principal title: "The sex peptide of Drosophila melanogaster: Investigation of post-mating responses of females using RNA interference."
Previous studies suggested that a "sperm effect" was responsible for the post-mating response. However, more recent work indicated that other components of ejaculatory fluid, including SP, also may play a role. To determine if SP accounts for the post-mating response, the teams used different methods to generate male fruit flies that do not produce SP. The UK co-authors employed the technique of RNA interference to insert a gene that suppresses SP production.
Their Swiss counterparts genetically engineered knockout flies lacking the gene for SP production. Both groups mated the SP-deficient males with virgin females and compared post-mating responses to females mated with male controls. They found that SP-deficient males produced a highly weakened post-mating response in females, even though the males transferred sperm during mating. These results indicate that the "sperm effect" is due to SP. However, because SP binds to sperm, the two groups propose that both SP and sperm are necessary for the normal post-mating response.