Extremely fragile bones are the reason why mainly children, but also adults with brittle bone disease will frequently break their bones, often even without any apparent injury. The genetic disease, also called osteogenesis imperfecta (OI), may present in varying forms from mild to severe and can also be associated with other symptoms including short height, hearing loss, skeletal deformity, loose joints, impaired vision and others. OI is a rare disease and affects 4 to 7 in 100.000 people. So far, a number of genes have been described in which defects might lead to disturbed bone formation and to the development of OI. Nevertheless, in some patients the underlying genetic cause remains unclear.

Led by the research group of Bernd Wollnik, Director of the Institute of Human Genetics at the University Medical Center Göttingen (UMG), a collaboration of scientists from Germany, Brazil, Portugal, UK and Switzerland has now discovered a novel gene involved in the development of OI. They studied five patients with progressive skeletal deformities who had suffered multiple bone fractures before their second year of life or even before birth, and they identified mutations in a novel gene: MESD. “We performed whole-exome sequencing in all patients, which means, we analyzed all coding regions of all 19.000 genes of the human genome in parallel. Before doing so, we had checked whether the patients carried any potentially disease-causing variations in genes that we already know to be connected with OI. They did not – but instead we discovered that they all had a mutation in both copies of the MESD gene. MESD has never before been linked to a human disorder, but we knew that it is involved in the WNT signaling pathway. This made it an excellent candidate for us”, describes Bernd Wollnik.

The WNT signaling pathway is a major network of various molecules and regulates fundamental cellular processes including embryonic development, cell differentiation and cell division. Although MESD is not a direct component of the WNT pathway, it acts indirectly within this network. As a chaperone protein it ensures that specific WNT receptor molecules, LRP5 and LRP6, adopt the protein folding they need for their correct functioning and that they traffic from the endoplasmatic reticulum to the cell membrane.

The researchers also performed detailed experiments in different animal models to elucidate the functional consequences of the identified mutation in cells. They showed that, due to their specific position in the protein, the mutations led to a reduction of MESD function but not to a complete loss. The role of WNT signaling in bone growth and strength had already been known. The Wollnik research group had in a previous study several years ago also demonstrated that a protein called WNT1, another component in this pathway, is relevant for bone formation and bone cell function.

So far there is no cure for OI. Therapy is based on surgery, physical therapy and medical treatment with bisphosphonates. However, in the current study, the use of bisphosphonates did not produce any positive effect. For Bernd Wollnik, this study also opens new perspectives for the treatment of OI: “Our cell experiments hint to a novel approach: Biological agents activating WNT signaling might be a potential treatment option for patients with MSED-associated OI.” Such a drug is already available and used to treat patients with aging-associated osteoporosis to increase bone formation and bone mass.

Bernd Wollnik and his research group at the Institute of Human Genetics in Göttingen have been intensively working on elucidating the genetic causes and molecular mechanisms of rare diseases. Their research focuses especially on disorders with premature aging (progeroid diseases), microcephalies and the biological processes underlying genomic instability.

The results of the current study have been published in The American Journal of Human Genetics.