Short Fingers indicated the Way

A freak of nature played an important role in their investigations. For generations, various members of an extended family living in Turkey inherited the disposition for severe hypertension. In addition, all afflicted family members — and only they — had strikingly short fingers, clinically termed brachydactyly. This characteristic spawned the search for specific genetic differences between afflicted and non-afflicted relatives. In the May issue of Nature Genetics Prof. Friedrich Luft at the Franz Volhard Clinic for Cardiovascular Diseases and his colleagues at the Max Delbrück Center for Molecular Medicine (MDC) in Berlin Buch report that they succeeded in localizing the responsible region on chromosome 12, one of the 23 chromosomes of which the human genome consists. The researchers will now identify, clone and finally sequence the respective gene. ​“We suggest that the identification of this gene will be of great relevance in elucidating new mechanisms of blood pressure regulation“, Prof. Luft pointed out.

In many cases, high blood pressure (hypertension) is at least partly influenced by genetics. According to experts, about 60 percent of all afflicted individuals have an inherited disposition for this disease. However, the hereditary rules are seldom as obvious as in the case of the family living on the Black Sea Coast in Turkey. Prof. Nihat Bilginturan, a Turkish doctor and scientist at the Hacettepe University School of Medicine in Ancara, described the family in the early 1970’s.

Various members of this family suffer from severe hypertension at a young age. At the age of 40 years, their blood pressure exceeds the normal value of ¹⁴⁰⁄₉₀ mm Hg by an average of 50 mm Hg. The consequences are drastic. None of the afflicted family members reaches the age of 50 years. Most die of stroke. Oddly enough, family members can easily tell in advance, who is affected because, unlike other patients suffering from hypertension, all affected family members have short fingers and toes.

The human geneticist Dr. Thomas Wienker from the Department of Medical Genetics at the MDC discovered Bilginturan’s publications a few years ago and initiated a new research project at the German institute. In autumn 1994, the MDC research group made their first journey to Turkey in order to examine the family described by Prof. Bilginturan. The scientists were able to collect medical data and information on more than 60 family members. The study provided abundant information for an unusually extended family tree spanning six generations. This pedigree reveals that the disease of the Turkish family is caused by a single gene (monogenetic) and that descendants will suffer from hypertension, even if they inherited the disposition from only one of their parents (dominant gene).

“There is no doubt that in this family hypertension and brachydactyly are closely related“, Dr. Wienker stressed. Still, it is unclear what is responsible for this genetic link. The scientists stated that one explanation might be the loss of a short stretch on the specific chromosome, affecting two closely situated genes. However, both traits might also result from changes in a single gene which influences different functions in the human body. Such ​“pleiotropic“ (Greek: ​“multiple”) gene functions are also known for other diseases.

The disease of the Turkish family does not correspond with either of the two forms of monogenetic hypertension discovered so far (aldosteronism and Liddle’s syndrome) nor with any other illness known to cause hypertension indirectly. This could be deduced from the presence of normal concentrations of the blood pressure regulating substances, renin and angiotensin, both in afflicted and in healthy members of the Turkish family. Moreover, it was observed that their hypertension was independent from the amount of salt intake.

Thus, the medical picture of their disease strongly resembles the condition of 95 percent of all patients suffering from hypertension. The causes of high blood pressure in these patients are unknown. In medical terms, this condition is called essential hypertension. Many experts believe that various factors, genetic as well as non-genetic, contribute to its development. Presumably, the gene responsible for the condition seen in the Turkish family also plays a crucial role in essential hypertension although; hypertension has nothing to do with finger length in other patients. Elucidating the genetic causes of the disease might therefore give new insight into the phenomenon of this disease.

To be able to define the position of the hitherto unknown hypertension gene, the scientists collected blood samples from the family members, extracted the chromosomes from the blood cells and analyzed the individual chromosomes for significant differences between afflicted and healthy individuals. The scientists used small specific pieces of hereditary material called microsatellite markers, to look for characteristic differences between the genetic patterns of various individuals. On chromosome 12 they detected a region which consistently differed in family members who suffered from hypertension and had short fingers from those of healthy family members. Recently, the researchers have located with a high degree of certainty a specific region in which the responsible disease gene resides.

The German researchers plan to identify the gene, clone it and finally elucidate its function. The afflicted members of the Turkish family have already profited from the German research project. The family members who suffer from hypertension are receiving cost-free medication to lower their blood pressure and protect them from early stroke.

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