Meet Ute Scholl, a 25 year old physician who defined a new clinical syndrome, and then identified the genetic mutations that cause the disease – all in less than one year.

Ute grew up in Aachen, Germany, interested in science and medicine. Hoping to combine the two, she attended medical school in Aachen and after a brief research fellowship in Hannover, came to the United States in March 2008 to work in Richard Lifton’s lab at Yale.

She plans to return to Germany in 2010 for a medical residency and ultimately hopes to work as a physician and a scientist, treating patients in the clinic and studying their disorders in the lab.

“Communication is a very important part of clinical medicine,” Ute told me, explaining why it’s important that she receive her clinical training in Germany, among German-speaking hospital staff and patients, rather than in the United States.

Ute is interested in identifying DNA mutations that cause kidney disease. There are hundreds of genetic diseases that affect the kidneys. For many we don’t know the cause and, consequently, have no cure.

After arriving at the Lifton laboratory, she was given a stack of hundreds of medical records of patients with kidney problems. Many patients displayed symptoms affecting other parts of the body also. Ute screened these records and found five people with similar symptoms: All suffered from seizures, deafness, ataxia (problems walking and controlling their limbs), mental retardation, and electrolyte imbalance (potassium and magnesium deficiencies and elevated blood pH, signs of kidney disease).

Nobody had ever described a disease with these symptoms. None of these patients have Bartter or Gitelman syndrome, diseases with similar electrolyte problems.

If this were the 19th century, Ute might have named the disease after herself and stopped there. But 21st century DNA sequencing and hybridization technology offers a chance to identify the underlying DNA mutation.

From the family history information, Ute and her colleagues thought the disease would be autosomal recessive, meaning the disease strikes males and females equally (so the mutation is not on the X or Y chromosome), and patients with the disease must possess two copies of the mutated gene, one inherited from each parent (homozygous). The parents, who don’t suffer from the disease, each have one normal copy of the gene and one mutated copy (heterozygous).

To identify the mutation, Ute and her colleagues looked for long stretches of DNA that were identical in both copies of a patient’s genome (homozygous). Every human genome contains differences in single bases of DNA scattered throughout. These differences, called single nucleotide polymorphisms, are often used to identify people in criminal investigations.

In this case, Ute was looking for a long stretch of homozygous single nucleotide polymorphisms in the same region of every patient’s genome, which would suggest that the identical piece of DNA was inherited from each parent. Odds are that the mutated gene would be found here.

The genome analysis, led by Murim Choi, identified a region of DNA with 2.5 million base pairs on chromosome 1, a region containing more than 70 genes. How to find the correct one? Ute took a candidate approach, guessing that if there was a single gene responsible for all the problems, it should be turned on in the relevant tissues, in this case the brain, ear and kidney.

Ion channels, a family of proteins that allow ions, such as potassium, to flow into and out of cells, fit the bill. (Some ion channels are specific for potassium, some for sodium, some for multiple ions, and so forth.) The brain, ear and kidney all require ion channels for proper function.

Among more than 70 genes in the region, there were two ion channels. Ute sequenced the KCNJ10, which codes for a well-understood channel that lets potassium ions into cells. gene

Lucky Ute. Every patient had two mutated copies of KCNJ10, and every mutation is predicted to interfere with its normal function. Unaffected parents had only one mutated copy, as you would expect.

Even luckier Ute. In 2000 other scientists genetically engineered mice lacking KCNJ10, and these mice had symptoms similar to the human patients. This saved Ute years of work and strongly supports the conclusion that mutations in KCNJ10 cause the human disease.

The frequency of this disease is unknown. Thus far there are only five known patients, but Ute hopes that her work will help physicians identify others. She is now studying how mutations in the KCNJ10 potassium channel cause this disease.

In the old school medical tradition, Scholl-Lifton syndrome would have been an acceptable name, harking back to the practice of naming diseases after those who describe them (such as Alzheimer’s, Parkinson’s and Creutzfeldt–Jakob diseases). Instead, Lifton has proposed the acronym SeSAME: Seizures, Sensorineural deafness, Ataxia, Mental retardation, Electrolyte imbalance.

Source: “Seizures, sensorineural deafness, ataxia, mental retardation, and electrolyte imbalance (SeSAME syndrome) caused by mutations in KCNJ10” by Ute I. Scholl, Murim Choi, Tiewen Liu, Vincent T. Ramaekers, Martin G. Häusler, Joanne Grimmer, Sheldon W. Tobe, Anita Farhi, Carol Nelson-Williams and Richard P. Lifton, published in PNAS online March 16 (doi: 10.1073/pnas.0901749106).