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Sci Rep. 2019 Jul 2;9(1):9569. doi: 10.1038/s41598-019-46004-2.

Epidemiological, Clinical and Genetic Study of Hypophosphatasia in A Spanish Population: Identification of Two Novel Mutations in The Alpl Gene.

Author information

1
University Hospital San Cecilio, Instituto de Investigación Biosanitaria (Ibs.GRANADA), Granada, Spain.
2
Fundación para la Investigación Biosanitaria de Andalucía Oriental (FIBAO), Granada, Spain.
3
Clinical Analysis Unit, University Hospital San Cecilio, Granada, Spain.
4
Department of Medicine, University of Granada, Granada, Spain.
5
Gene Regulation, Stem Cells & Development Lab, GENYO, Centre for Genomics and Oncological Research: Pfizer-University of Granada-Andalusian Regional Government, Granada, Spain.
6
Department of Biochemistry and Molecular Biology I, University of Granada, Granada, Spain.
7
Pediatric Unit, University Hospital San Cecilio, Granada, Spain.
8
University Hospital San Cecilio, Instituto de Investigación Biosanitaria (Ibs.GRANADA), Granada, Spain. bgfontana@fibao.es.
9
CIBERFES, Instituto de Salud Carlos III, Granada, Spain. bgfontana@fibao.es.
10
CIBERFES, Instituto de Salud Carlos III, Granada, Spain.
11
Endocrinology and Nutrition Unit, University Hospital San Cecilio, Granada, Spain.

Abstract

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.

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