Cause of rare disorder SOFT syndrome discovered

The genetic mutation that causes the rare disorder called SOFT syndrome has been discovered by a team at Tel Aviv’s Sourasky Medical Center and Afula’s Emek Medical Center, which will help those with a history of the disease spare future family members.

The researchers were led by Sourasky Dermatology Department chairman Prof. Eli Sprecher and Prof. Stavit Shalev, director of Emek’s Genetics Institute, who published their findings this week in the American Journal of Human Genetics. The disease was found in two Muslim families who had inbred and married first cousins, and the discovery of its cause illuminates the connection between skin and bone.

It took the team almost seven years to decipher the molecular underpinning of the “orphan,” or rare, disorder.

People with SOFT syndrome have a host of symptoms represented by the acrostic, including: disproportionately short stature, clinical skeletal (S) and nonskeletal manifestations; abnormal nails (onychodystrophy or O); unusual facial traits (facial dysmorphism or F); and sparse hair (hypotrichosis or T). Children with the syndrome reach their maximum height between the age of six to eight years. Their head circumference is small and they have a long, triangular face with a prominent nose.

They often also have unusually high-pitched voices, small ears and abnormal fingers, although their psychomotor development is normal.

The disorder causes retardation in fetal growth that is clear via ultrasound. Couples aware of the existence of the syndrome in their family will now be able to take advantage of prenatal genetic diagnosis, the researchers said, which will help them discern fetal health and whether to undergo in-vitro fertilization.

To understand the disorder, imagine that you have been asked to build a large edifice with hundreds of separate rooms dedicated to distinct activities. Clearly, the shape and arrangements of these rooms will differ, but the materials used to build most of them will be similar. Sharing materials is also at the core of the process through which most human tissues are generated and regenerated over the course of a lifetime.

For this reason, the usage of any defective component in this process is likely to affect the composition of more than one single tissue – or to lead to a disease with various and apparently unrelated symptoms. The study of such disorders was very likely to reveal intersecting biological pathways of importance for the normal functioning of the human body, the researchers said.

Six years ago, Sprecher and Shalev decided to join forces to elucidate the molecular basis of a complex condition, about which little was known but was found among some Israeli families. Using advanced technologies, the researchers discovered that the disease resulted from the defective functioning of a protein called POC1A.

Dr. Ofer Sarig, who led the final and successful phase of this research program, said: “We discovered that in the absence of POC1A, the patient cells replicate very slowly, which of course very nicely fits the clinical phenotype displayed by affected individuals – who suffer from arrested growth of bone, nails and hair. In addition, together with Prof. Mia Horowitz and Dr. Debbie Rapaport at Tel Aviv University, we were able to show that POC1A apparently also plays a critical role in the molecular assembly of a critical component of our cells, known as the Golgi apparatus, which is required for proper trafficking of proteins in and out of our cells.”

“This has been a long – at some points, very frustrating – journey,” concluded Sprecher. “But at the end of the day, the result was worth all of our efforts. We will now be able to provide affected families with proper genetic counseling, and, not less importantly, we have now added a new and important piece to our understanding of the way skin and bone develop and interact during the formation of our body tissues.”