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Clinical applications (C. Collet, P. Orcel, M-C de Vernejoul, in collaboration with M. Cohen-Solal)

The department of molecular biology of Lariboisière Hospital performs the molecular diagnosis of several genes implicated in hereditary bone diseases such as lrp5, sost, Clc7, cathepsin K, Fgfr3… We are the only national diagnostic lab that proposes the LRP5 gene analysis which is implied in different rare pathologies such as osteoporosis pseudo glial (OPPG) and osteopetrosis type I.

Considering also the recruitment of the rheumatology department of Lariboisière and our role in the French “reference center for constitutional bone diseases”, we will develop two research programs :

1. The role of LRP5 variants in osteoporosis in young adults: Our preliminary data from 50 young patients affected by idiopathic osteoporosis with fractures, demonstrated a mutation in the LRP5 gene in 10 % of case. Our project will be to perform the LRP5 gene analyses from a large cohort in collaboration with Dr Uwe Kornak (Charité hospital, Berlin). We will also perform a functional analysis of the new variants we observed. In case of positive results, the dosages of the different bone markers will be determined in order to more precisely define the phenotype of this type of osteoporosis.

2. Finding a new gene responsible for osteopetrosis: Also in collaboration with the Charité Hospital in Berlin, we collected patients with autosomal dominant osteopetrosis that are negative for the ClCN7 mutation. The objective is to identify new genes controlling bone resorption. Our part in this project will be to perform an exome sequencing of 5 families of patients recruited in Lariboisière with a very homogenous bone phenotype and negative for the CLCN7 mutation.

3. Within the Reference Centre for Constitutional Bone diseases, we follow a cohort of more than 150 patients with fibrous dysplasia, a genetic, non-inherited rare bone disease associated with activating missense mutations of the GNAS gene (Chapurlat & Orcel, 2008). These patients exhibit various bone phenotypes. We are coordinating a European clinical trial evaluating the effect of an oral bisphosphonate, risedronate, on bone pain and on the evolution of osteolytic bone lesions, the PROFIDYS trial, sponsored by the Inserm with an important funding from the PHRC. In these patients, clinicians are lacking tools enabling them to predict the outcome. It is therefore our goal to take advantage of this well characterized cohort of patients to develop reliable biomarkers, which could be helpful for clinicians to ascertain the diagnosis and prognosis of bone involvement in fibrous dysplasia.

4. To identify determinants of bone fragility in primary hyperparathyroidism. In this disease, the risk of fracture is poorly predicted with bone mineral densitometry. Moreover, the exact bone benefit of parathyroidectomy is unknown. The aim is to determine the changes induced by parathyroidectomy in cortical and trabecular bone. We will analyse the parameters of bone microarchitecture with micro-scanner of patients with HPTP and the change one year with or without parathyroidectomy. This project is a PHRC obtained in 2011 (MicroOS) by M.  Cohen-Solal in collaboration with G. Maruani (physiology laboratory, G. Pompidou's hospital.