Advanced studies for biochemical understanding and biomarkers identification in XLH - the most prevalent form of hereditary human rickets

• Grant number: 24/01497-0
• Support Opportunities: Regular Research Grants
• Start date: October 01, 2024
• End date: September 30, 2026
• Field of knowledge: Biological Sciences - Biochemistry - Enzymology
• Principal Investigator: Nilana Meza Tenório de Barros Jaggi
• Grantee: Nilana Meza Tenório de Barros Jaggi
• Host Institution: Instituto de Ciências Ambientais, Químicas e Farmacêuticas (ICAQF). Universidade Federal de São Paulo (UNIFESP). Campus Diadema. Diadema , SP, Brazil
• Associated researchers: João Bosco Pesquero

Abstract

Classified as a rare disease (RD) (1:20,000), X-Linked Hypophosphatemia (XLH) corresponds to the most prevalent form of hereditary rickets in humans, representing approximately 80% of familial rickets cases. XLH patients present severe defects in phosphate reabsorption and vitamin D metabolism, growth retardation, osteomalacia, bone abnormalities, severe bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis and muscle dysfunction, consequently resulting in significant loss of their quality of life from childhood (generally from 2 years of age). Lastly, like other RD(s), XLH can be progressive, disabling, degenerative and also lead to death, and finding an accurate diagnosis is often a slow process.The PHEX gene (Xp22.1) was identified in 1995 as the mutated gene responsible for XLH. However, until now, the mechanisms of how the mutation of this gene results in the biochemical and clinical characteristics of this anomaly have not been elucidated. This gene encodes the membrane metallopeptidase PHEX (E.C. 3.4.24.B15), which had its first protein substrate identified through the support received at my first FAPESP project (Projeto Regular 2011-2013) (Barros et.al., 2013). Although I had to temporarily stop research due to serious family health issues, previously I had the opportunity to publish important articles, and also make progress in identifying a biomarker in the serum of XLH patients. The present request support in this new phase, is essential for the reopening of this research and consequently for my scientific career. Although we already have robust preliminary data, these still need to be effectively finalized and complemented. In this second Fapesp project, we aim to expand the scope of the study of biomarkers, identify new substrates (already pre-analyzed) and investigate the influence of this new biomarker on phosphate loss (as a future target for treatments).In this project, we are also committed to contributing for more diagnoses of XLH patients, also supporting the mapping of this disease in Brazil. This study will contribute significantly to the XLH understanding and can highlight key molecules for future effective new treatments, and is directly connected to the improvement of health and well-being, and reduction of inequalities (objectives 3 and 10, respectively, among the Sustainable Development Goals (SDGs). (AU)