**Hypophosphatasia: A Systemic Skeletal Disorder Caused by Alkaline Phosphatase Deficiency Caused by Alkaline Phosphatase Deficiency**

**Hypophosphatasia: A Systemic Skeletal Disorder** 

DOI: 10.5772/intechopen.70597

#### Hideo Orimo Hideo Orimo Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.70597

#### **Abstract**

Hypophosphatasia (HPP) is an inherited systemic bone disease caused by the deficiency of tissue-nonspecific alkaline phosphatase (TNAP). HPP is classified into six forms and the symptoms of HPP vary depending on the form. The pathophysiology of HPP is basically due to a defect of bone mineralization. TNAP is encoded by the *ALPL* gene, and the TNAP protein expressed in bone, kidney, liver, and neuronal cells and is linked to the cell membrane via a glycosylphosphatidylinositol anchor. TNAP is an ectoenzyme hydrolyzing phosphate compound such as inorganic pyrophosphate. TNAP plays an important role in mineralization of hard tissues. Defect of mineralization process causes hypomineralization of hard tissues, which leads to rickets or osteomalacia and dental manifestations. In addition, hypomineralization of the ribs results in respiratory failure in the severe forms, which is the main cause of death. Inheritance of HPP is autosomal recessive, but autosomal dominant cases have been reported in the milder forms. To date, a total of 335 mutations in the *ALPL* gene have been reported, and mutation sites are scattered throughout the gene. Recent development of enzyme replacement therapy has opened up a new vista on the treatment of this previously untreatable disease.

**Keywords:** hypophosphatasia, alkaline phosphatase, mineralization, bone, enzyme replacement therapy

#### **1. Introduction**

Hypophosphatasia (HPP; Online Mendelian Inheritance in Man (OMIM) #241500,241,510, 146,300) is an inherited systemic bone disease that is due to a deficiency of tissue-nonspecific alkaline phosphatase (TNAP) [1–3]. The first case of HPP was reported by the Canadian pediatrician John Campbell Rathbun in 1948 as a new developmental anomaly [4]. That case was an infantile form, and the patient's mutations were identified 50 years later using DNA

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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons

of the surviving parents as a compound heterozygote of p.A114T and p.D294A [5]. Since then, a total of 335 mutations in the gene for TNAP (the *ALPL* gene) have been reported [6]. The symptoms of HPP vary and are classified into six HPP forms [1, 2]. The pathophysiology of HPP is basically due to a defect of bone mineralization. In severe forms, the patients show skeletal manifestations and respiratory failure derived from costal bone insufficiency, whereas in the mildest forms, they show only dental manifestations [1]. Recent development of enzyme replacement therapy (ERT) has opened up a new vista on the treatment of this previously untreatable disease [7].

Retinoic acid regulates the expression of TNAP via RARE [15], whereas another fat-soluble vitamin, active vitamin D (1,25-dihydroxycholecalciferol), regulates the expression of TNAP by modification of the stability of TNAP mRNA [16]. Furthermore, phosphates derived from ALP enzymatic activity are considered to regulate TNAP expression [17]. Epigenetic regulation by methylation of some of the promoter regions of the gene has been reported [18]. However, the precise regulatory mechanism of the *ALPL* gene regulation, especially its tissue-specific regulation, is not known. On the other hand, the genes encoding tissue-specific ALPs are located on the long arm of chromosome 2 and have a more

Hypophosphatasia: A Systemic Skeletal Disorder Caused by Alkaline Phosphatase Deficiency

http://dx.doi.org/10.5772/intechopen.70597

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The TNAP protein, which has a molecular weight of approximately 80 kDa, is linked to the outer cell membrane through a glycosylphosphatidylinositol (GPI) anchor [9]. The TNAP protein is initially synthesized as a 66 kDa peptide, and then *O*- and *N*-glycosides are attached in the endoplasmic reticulum. Eventually, TNAP is localized on the outer membrane of the cells via a GPI anchor [23]. This GPI anchor is added after hydrophobic amino acid residues at the C-terminus are eliminated. The GPI anchor consists of an ethanolamine phosphate, three residues of mannose, a glucosamine, and a phosphatidylinositol [9]. The precise amino acid residue in TNAP to which the GPI anchor is added has not been elucidated, whereas it is known to be an aspartate residue (D484) in PLAP [24, 25]. An active enzyme consists of a dimer and acts as an ectoenzyme. Approximately 58% of the amino acid residues in human TNAP sequences are conserved among mammalian ALPs [26]. On the other hand, approximately 90% of the amino acid residues are conserved among mammalian TNAPs, which allow prediction of missense mutations responsible for HPP [26]. Since the three dimensional structure of TNAP has not been solved, a simulation model based on human PLAP or mouse IAP is used to discuss TNAP structure [27–29]. The active site of the enzyme comprises a catalytic serine residue (S92 in the human PLAP), two Zn2+-binding sites, and an Mg2+-binding site. Ca2+ is also necessary as a cofactor. The crown domain is characteristic of mammalian ALPs and is considered to interact with extracellular proteins including collagen [30]. There are also isoforms of TNAP itself that depend on the tissue origin. Since these isoforms have different *O*-linked sugar chains, they show different patterns

The systematic name of ALP is orthophosphoric-monoester phosphohydrolase [alkaline optimum] (EC 3.1.3.1) that hydrolyzes monophosphate esters, and the optimal pH is between 8 and 10 [9]. Inorganic pyrophosphate (PPi) and pyridoxal 5′-phosphate (PLP) are considered to be natural substrates of the enzyme [32]. PPi is an inhibitor of hydroxyapatite formation, which is essential for bone mineralization. PLP is an active vitamin B6 and is necessary in neuronal cells for the biosynthesis of γ-aminobutyric acid (GABA), which acts as an inhibitory neurotransmitter. PLP on the outside of neuronal cells must be dephosphorylated by TNAP at the cell membrane before it can enter the neuronal cells, and it is then be rephosphorylated within the neuronal cells [32, 33]. In laboratory testing, ALP enzymatic activity is usually estimated using *p*-nitrophenylphosphate as an artificial

compact gene structure [19–22].

on the electrophoresis. [9, 31].

substrate [9].
