Abstract
Summary
Using genetic, clinical, biochemical, and radiographic assessment and bioinformatic approaches, we present an unusual case of adult HPP caused by a novel de novo heterozygous nonsense mutation in the alkaline phosphatase (ALPL).
Introduction
Hypophosphatasia (HPP) is caused by genetic alterations of the ALPL gene, encoding the tissue-nonspecific isozyme of alkaline phosphatase (TNSALP). Here, the purpose was to perform clinical and molecular investigation in a 36-year-old Caucasian woman suspected to present adult HPP.
Methods
Medical and dental histories were obtained for the proposita and family members, including biochemical, radiographic, and dental assessments. ALPL mutational analysis was performed by the Sanger sequencing method, and the functional impact prediction of the identified mutations was assessed by bioinformatic methods.
Results
We identified a novel heterozygous nonsense mutation in the ALPL gene (NM_000478.6:c.768G>A; W[TGG]>*[TGA]) associated with spontaneous vertebral fracture, severe back pain, musculoskeletal pain, low bone density, and short-rooted permanent teeth loss. Functional prediction analysis revealed that the Trp256Ter mutation led to a complete loss of TNSALP crown domain and extensive loss of other functional domains (calcium-binding domain, active site vicinity, and zinc-binding site) and over 60% loss of homodimer interface residues, suggesting that the mutant TNSALP molecules are nonfunctional and form unstable homodimers. Genotyping of the ALPL in the proposita’s parents, sister, and niece revealed that in this case, HPP occurred due to a de novo mutation.
Conclusion
The present study describes a novel genotype-phenotype and structure-function relationship for HPP, contributing to a better molecular comprehension of HPP etiology and pathophysiology.
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Acknowledgments
We thank the proposita’s family for their participation in this study. We thank Ricardo Zylbergeld (LudoLab - interactive and immersive experiences, http://www.ludolab.com.br/) for technical assistance in building the web interface-based 3D interactive software.
Funding
This research was supported by the National Council for Scientific and Technological Development [CNPq, grant no. 304680/2014-1 (FHNJ)], by Coordination for the Improvement of Higher Education Personnel [CAPES, grant no. 33003033008P8 (LM)], and by NIDCR/NIH grant R03DE028411 (BLF).
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The study was conducted in compliance with the recommendation of the World Medical Association Declaration of Helsinki, Ethical Principles for Medical Research Involving Human Subjects, and written informed consent or assent was obtained for the individuals enrolled to report their clinical data, retrospective medical histories, and genetic information. The study protocol was approved by the Piracicaba Dental School - State University of Campinas Institutional Review Board (IRB#88910618.0.0000.5418).
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ESM 1
ALPL mutation analysis and segregation pattern. (A) Pedigree representation of the enrolled subjects in generations I-III, including the proposita (arrow). Black shading indicates symptomatic individuals. (B) Representative electropherograms showing that the proposita is the only carrier of the p.Trp246Ter heterozygous nonsense mutation (pathogenic) in the pedigree. (C) Representative electropherograms showing that the proposita also carries the heterozygous missense variation p.Val522Ala (benign), which was inherited from her father (I.1). The mother (I.2) has a native genotype for both alterations. (PNG 703 kb)
ESM 2
Residue conservation analysis for Val522 residue affected by ALPL mutation in the proposita. (A) The residue conservation within the human genome between paralogous sequences ALPL, ALPI, ALPP, and ALPPL, is displayed by multiple sequence alignment. (B) Residue conservation of orthologous ALPL sequences across 20 vertebrate species is shown. Val522 (highlighted by a black rectangle) is not highly conserved among vertebrate species. (PNG 1103 kb)
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Martins, L., dos Santos, E., de Almeida, A. et al. A novel de novo heterozygous ALPL nonsense mutation associated with adult hypophosphatasia. Osteoporos Int 31, 2251–2257 (2020). https://doi.org/10.1007/s00198-020-05490-1
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DOI: https://doi.org/10.1007/s00198-020-05490-1