Genetics of Bone Formation and Bone Density
The bone mass of our body is regulated via complex feedback loops, loss of bone results in osteoporosis, a condition that is invariably associated with ageing and that results in an increased susceptibility to fractures. To elucidate the molecular processes that govern osteoporosis and ageing in bone, we are studying the genetic causes of abnormal bone density. We have been able to identify disease-causing mutations in several different genes (GORAB, ATP6V0A2, PYCR1, WNT1), two of which are involved in the Golgi network. Our findings provide new insights into the molecular mechanisms of skin ageing and osteoporosis. Increased susceptibility to apoptosis and/or senescence appears to be an important trigger for age-related changes in skin and bone. Current studies focus on the identification of novel disease genes and the characterization of pathogenic mechanisms in osteoporosis, in particular, related to senescence. Studies are being carried out to determine the prevalence of mutations in patients with early-onset osteoporosis.
Wnt1 is an Lrp5-independent bone-anabolic Wnt ligand.
Sci Transl Med. 2018 Nov 7;10(466). pii: eaau7137
Impaired proteoglycan glycosylation, elevated TGF-β signaling, and abnormal osteoblast differentiation as the basis for bone fragility in a mouse model for gerodermia osteodysplastica.
PLoS Genet. 2018 Mar 21;14(3):e1007242
Noncoding copy-number variations are associated with congenital limb malformation.
Genet Med. 2018 Jun;20(6):599-607. Epub 2017 Oct 12
De Novo Mutations in SLC25A24 Cause a Craniosynostosis Syndrome with Hypertrichosis, Progeroid Appearance, and Mitochondrial Dysfunction.
Am J Hum Genet. 2017 Nov 2;101(5):833-843
The progressive ankylosis protein ANK facilitates clathrin- and adaptor-mediated membrane traffic at the trans-Golgi network-to-endosome interface.
Hum Mol Genet. 2016. pii: ddw230.
A de novo 1q23.3-q24.2 deletion combined with a GORAB missense mutation causes a distinctive phenotype with cutis laxa.
J Hum Genet 2017 Feb;62(2):325-328
Recurrent De Novo Mutations Affecting Residue Arg138 of Pyrroline-5-Carboxylate Synthase Cause a Progeroid Form of Autosomal-Dominant Cutis Laxa.
Am J Hum Genet. 2015 Sep 3;97(3):483-92
Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3.
Brain. 2014 Mar;137(Pt 3):683-92. Epub 2014 Jan 22.
Multiscale, converging defects of macro-porosity, microstructure and matrix mineralization impact long bone fragility in NF1.
PLoS One. 2014 Jan 21;9(1):e86115. eCollection 2014.