If several children in one family develop a disease that normally occurs among older people, this arouses the attention of genetic experts. Especially if the parents of the diseased children are blood relatives, the suspicion arises that the disease may be inherited. The teams led by Professor Ludger Schöls of the Hertie Institute of Clinical Brain Research at the University of Tübingen and the German Center for Neurodegenerative Diseases and Dr. Holger Prokisch of Helmholtz Zentrum München and the German Center for Diabetes Research (DZD), learned of a family in which three of four children suffered from early-onset diabetes. In addition, all three had a hearing loss since early childhood. They also suffered from gait disorders and had problems with goal-directed movements, called ataxia.
To find the responsible genetic mutation, the Tübingen and Munich researchers sequenced the exome of two of the three siblings. Although the exome comprises only about one percent of the human genome, it contains most of the disease-causing genetic alterations (mutations) that have so far been identified. Both siblings had a mutation in the DNAJC3 gene. “Although the gene had already been found to be associated with diabetes in animal models, its effect was unclear in humans,” said Dr. Holger Prokisch, the last author of the study. “Deletion of the gene leads to the destruction of the beta cells, which produce insulin in the pancreas.”
The DNAJC3 gene contains the information for a chaperone protein. This is the term biologists use to designate proteins that help the newly generated proteins fold and support them in the degradation of misfolded proteins. The mutation, which the researchers also discovered in the third affected sibling, leads to the absence of the co-chaperone DNAJC3. Due to a so-called loss-of-function mutation, only an abbreviated DNAJC3 protein is formed which has no value for the cell.
“Since the DNAJC3 protein is involved in the correct folding of a variety of proteins, the consequences are serious," explained Dr. Matthis Synofzik from the Hertie Institute for Clinical Brain Research in Tübingen and the Tübingen site of the German Center for Neurodegenerative Diseases. Not only were the insulin-producing cells in the pancreas affected, but also various types of nerve cells. The MRI revealed an atrophy in the cerebellum, which among other things is responsible for the coordination of movements. “That explains the gait disorders and ataxia," said Synofzik, lead author of the study. He assumes that the cerebrum is also affected, because patients had difficulties with computing tasks. A decreased nerve conduction velocity showed that not only the central nervous system, but also the peripheral nerves in the arms and legs were damaged. All of the affected children were remarkably small for their age. This suggests that growth disorders were also part of the clinical picture.
To find out if this is an isolated case, the researchers screened the German multicenter DPV (Diabetes Patienten Verlaufsdokumentation) registry, a database with 226,194 diabetes patients in Germany. There they found 35 individuals with a similar clinical picture, of which eight were willing to undergo genetic analysis. In one of these patients a defect in the DNAJC3 gene was also found. However, it was not a point mutation like in the first family, but a deletion, in which whole segments of the gene are lost. Further research revealed that the sister was also affected and had the same deletion. The parents of the siblings were first cousins, and thus also blood relatives.
Why the mutation “only” causes cell death in the pancreas and in the brain is still unclear. Connective tissue cells of the skin were normal, although the DNAJC3 protein was absent here, too. According to Synofzik, the newly discovered gene mutation resembles the Wolfram sydrome 1, in which children develop hearing loss and visual disorders along with early onset diabetes. Here, too, research results show that the responsible genetic defect leads to a disturbance in protein production. The defect in the DNAJC3 gene shall in the future serve as an important model for investigating the common cause of diabetes and neurodegeneration.
The central research institutions involved in the study are the Hertie Institute for Clinical Brain Research at the University of Tübingen, the Center for Rare Diseases in Tübingen, the German Center for Diabetes Research at the sites in Tübingen, Munich and Miami, Helmholtz Zentrum München and the American Institute of Human Genetics in Miami.
Synofzik, M. et al. (2014). Absence of BiP Co-chaperone DNAJC3 Causes Diabetes Mellitus and Multisystemic Neurodegeneration, American Journal of Human Genetics, doi 10.1016/j.ajhg.2014.10.013