Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene
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AuthorGarcía Fontana, Cristina; Villa Suárez, Juan M.; Andujar Vera, Francisco; González Salvatierra, Sheila; Martínez Navajas, Gonzalo; Real, Pedro J.; Gómez Vida, José María; de Haro, Tomas; García Fontana, Beatriz; Muñoz-Torres, Manuel
García-Fontana, C., Villa-Suárez, J. M., Andújar-Vera, F., González-Salvatierra, S., Martínez-Navajas, G., Real, P. J., ... & Muñoz-Torres, M. (2019). epidemiological, Clinical and Genetic study of Hypophosphatasia in A spanish population: Identification of Two Novel Mutations in the Alpl Gene. Scientific reports, 9(1), 9569.
SponsorshipResource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco (with support from NIH P41-GM103311); grants from Alexion and FEIOMM, by Instituto de Salud Carlos III (grants PI18-00803 and PI18-01235); co-funding from FEDER and by Junta de Andalucía (grant PI-0207-2016); GM-N is supported by the predoctoral program from Instituto de Salud Carlos III (FI17/00178) and by the Research Initiation Grants for Official Master Students program from the University of Granada (2017); PJR is a Ramon y Cajal Researcher from the MINECO (RYC-2015-18383) at GENyO and University of Granada.
Hypophosphatasia (HPP) is a genetic disease caused by one or several mutations in ALPL gene encoding the tissue-nonspecific alkaline phosphatase affecting the mineralization process. Due to its low prevalence and lack of recognition, this metabolic disorder is generally confused with other more frequent bone disorders. An assessment of serum total alkaline phosphatase (ALP) levels was performed in 78,590 subjects. Pyridoxal-5′-phosphate (PLP) concentrations were determined and ALPL gene was sequenced in patients potentially affected by HPP. Functional validation of the novel mutations found was performed using a cell-based assay. Our results showed persistently low serum ALP levels in 0.12% of subjects. Among the studied subjects, 40% presented with HPP-related symptoms. Nine of them (~28%) had a history of fractures, 5 (~16%) subjects showed chondrocalcinosis and 4 (~13%) subjects presented with dental abnormalities. Eleven subjects showed increased PLP concentrations. Seven of them showed ALPL gene mutations (2 of the mutations corresponded to novel genetic variants). In summary, we identified two novel ALPL gene mutations associated with adult HPP. Using this protocol, almost half of the studied patients were diagnosed with HPP. Based on these results, the estimated prevalence of mild HPP in Spain could be up to double than previously reported.