Metabolic Bone Diseases

In many of the families, we have identified the disease-causing gene variant. We have described a heterozygous missense mutation in WNT1 that leads to aberrant WNT signaling and causes an abnormal skeletal phenotype in children and young adults, and several mutations in the X-chromosomal PLS3, causing severe osteoporosis in boys and men. Additionally, we have recently identified heterozygous pathogenic variants in SGMS2 leading to altered sphingolipid metabolism and causing through yet unknown mechanism childhood-onset osteoporosis with or without complex skeletal dysplasia. By exome and whole-genome sequencing studies we have identified several new genes associated with early-onset osteoporosis and studies are ongoing in other families with unidentified genetic causes.

Further studies have revealed altered levels of bone biomarkers FGF23 and DKK1 in WNT1-and PLS3-related osteoporosis, respectively, as well as altered microRNA profiles in these monogenic forms of osteoporosis. These results provide new insights to the mechanisms behind the skeletal pathologies. Currently, we have ongoing in vitro and in vivo studies on WNT1, PLS3, and SGMS2, through national and international collaborations.

We have also studied the role of LRP6, FGF23, WNT16, CRTAP, and several other genes in early-onset osteoporosis and have investigated the effect of genetic variation on bone mineral density and mineral homeostasis in children and adolescents. In addition, we showed that genetic variation in the vitamin D binding protein affects vitamin D status and the response to vitamin D supplementation in infants. Furthermore, we have several other ongoing genetic studies on childhood obesity and bone metabolism, short stature, skeletal dysplasias, and endocrinopathies. For instance, we participated in an American study that identified a new genetic defect that caused growth disorders and a completely new genetic disease. An article published in the journal Science describes the results of the international collaborative study, in which genetic defects in the GNAI2 gene were identified in 20 patients. This study describes a new syndrome belonging to the so-called rasopathies class, which, in addition to growth, involves dysfunction of several organs and systems, notably the immune system.