News Release

Many kidney diseases causes by single gene defects, thus treatments can be targeted to these defects

Peer-Reviewed Publication

The Lancet_DELETED

The first paper in The Lancet Series on Renal Medicine discusses genetic kidney diseases, and highlights that recently many such diseases have been shown to be single gene defects. Knowledge of a disease-causing mutation in a single-gene disorder represents one of the most robust diagnostic examples of personalised medicine because the mutation conveys an almost 100% risk of developing the disease by a defined age, says paper author Professor Friedhelm Hildebrandt, Howard Hughes Medical Institute at the University of Michigan Health System, Ann Arbor, MI, USA.

Because of the strong genotype-phenotype correlation of almost 100% that is noted in recessive single-gene renal disorders, mutation analysis reveals the primary cause of the disease, allows prenatal diagnostic tests to be done, and has a high diagnostic and prognostic value—with mutations conveying an almost 100% risk of developing, for example, autosomal recessive polycystic kidney disease.

Single-gene defect kidney diseases are grouped according to main diagnostic features. Glomerular diseases are those that affect the kidney's filtering apparatus and include steroid-resistant nephrotic syndrome, which usually manifests as focal segmental glomerulosclerosis, a replacement of the filtering units by scar tissue. In children, this is associated with a 30% risk of recurrence in a kidney transplant. Facial swelling, low blood proteins, abnormal blood fats, and high blood pressure can all be symptoms.

Renal cystic ciliopathies are those kidney diseases involving cysts, rounded hollow spaces in the kidney. For example, autosomal dominant polycystic kidney disease (ADPKD) is the most frequent lethal heritable dominant disease in the USA and Europe, affecting about 1 in 1000 people. Chronic kidney disease develops by age 60—70 years. 90% of ADPKD cases can now be diagnosed by mutation testing, which is helpful for clinical decision making, especially in living-related donor transplantation.

Renal tubular disorders affect reuptake of water, salt, and sugars from the glomerular filtrate (the fluid in the kidney post-filtration). In such disorders, the primary genetic defect causes loss of function of a specific renal transport protein or signalling molecule. For example, sodium reabsorption abnormalities cause Bartter's syndrome leading to loss of salt from the kidneys.

Congenital abnormalities of kidney and urinary tract are responsible for almost 50% of cases of end-stage kidney disease in children. These abnormalities arise in about three to six per 1000 livebirths and constitute 20󈞊% of all anomalies identified in newborn babies. A wide range of conditions can be caused by such abnormalities.

The author says: "An important feature of monogenic diseases is that the mutation represents the primary cause of the disease, and therefore provides opportunities for diagnosis, treatment, and insights into pathogenesis ... New drugs can be developed—eg, by analysis of animals in which the gene of interest has been deactivated."

Disease-causing genes of recessive single-gene disorders are rarer than polygenic disorders, manifest early in life, cause disease in almost every individual with the genetic defect, are seldom associated with environmental effects, and are usually detected by gene mapping. By contrast, multi-gene (polygenic) disorders are more common, manifest later in life, exert weak causality on the disease phenotype, are commonly associated with environment effects, and are usually detected by genome-wide association studies. Many such studies have been published in the last few years.

Professor Hildebrandt concludes by discussing a new technique—exome capture—that will greatly assist the rapid discovery of causative genes for single-gene disorders. Exome capture allows selecting only the segments of the human DNA that codes for proteins, thereby reducing gene discovery to the relevant part of the genome. Combined with large-scale gene sequencing, Professor Hildebrandt says that exome capture 'will assist disease gene discovery in the future. This approach will further help molecular genetic diagnosis, enhance our understanding of disease mechanisms, and thus enable the development of new targeted drugs. It will also provide guides for mutation-specific prognosis and treatment'.

###

Professor Friedhelm Hildebrandt, Investigator, Howard Hughes Medical Institute at the University of Michigan Health System, Ann Arbor, MI, USA. T) +1-734-764 7145 E) fhilde@umich.edu

For full Series paper 1, see: http://press.thelancet.com/renal1.pdf


Disclaimer: AAAS and EurekAlert! are not responsible for the accuracy of news releases posted to EurekAlert! by contributing institutions or for the use of any information through the EurekAlert system.