ALPL
Identifiers
Aliases	ALPL, AP-TNAP, APTNAP, HOPS, TNAP, TNSALP, alkaline phosphatase, liver/bone/kidney, TNALP, alkaline phosphatase, biomineralization associated, HPPA, HPPI, HPPC, HPPO, TNS-ALP
External IDs	OMIM: 171760 MGI: 87983 HomoloGene: 37314 GeneCards: ALPL
Gene location ( Human) Chr. Chromosome 1 (human) [1] Band 1p36.12 Start 21,509,397 bp [1] End 21,578,410 bp [1]
Gene location ( Mouse) Chr. Chromosome 4 (mouse) [2] Band 4 D3|4 70.02 cM Start 137,469,044 bp [2] End 137,523,695 bp [2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in right adrenal gland right lobe of liver upper lobe of lung upper lobe of left lung blood right lung lower lobe of lung spleen kidney tibia Top expressed in molar calvaria body of femur kidney facial skeleton ankle blastocyst nasal septum ankle joint Meckel's cartilage More reference expression data BioGPS More reference expression data
Gene ontology Molecular function protein binding metal ion binding hydrolase activity alkaline phosphatase activity catalytic activity pyrophosphatase activity phosphatase activity Cellular component integral component of membrane anchored component of membrane membrane extracellular membrane-bounded organelle extracellular exosome extracellular region extracellular space plasma membrane extracellular matrix Biological process response to lipopolysaccharide osteoblast differentiation biomineral tissue development cementum mineralization cellular response to organic cyclic compound skeletal system development metabolism dephosphorylation response to vitamin D response to antibiotic developmental process involved in reproduction response to glucocorticoid endochondral ossification C-terminal protein lipidation Sources: Amigo / QuickGO
Orthologs Species Human Mouse Entrez 249 11647 Ensembl ENSG00000162551 ENSMUSG00000028766 UniProt P05186 P09242 RefSeq (mRNA) NM_000478 NM_001127501 NM_001177520 NM_001369803 NM_001369804 NM_001369805 NM_001287172 NM_001287176 NM_007431 RefSeq (protein) NP_000469 NP_001120973 NP_001170991 NP_001356732 NP_001356733 NP_001356734 NP_001274101 NP_031457 Location (UCSC) Chr 1: 21.51 – 21.58 Mb Chr 4: 137.47 – 137.52 Mb PubMed search [3] [4]
Wikidata
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Alkaline phosphatase, tissue-nonspecific isozyme is an enzyme that in humans is encoded by the ALPL gene. ^{[5] [6]}

Function

There are at least four distinct but related alkaline phosphatases: intestinal, placental, placental-like, and liver/bone/kidney (tissue-nonspecific). The first three are located together on chromosome 2, whereas the tissue-nonspecific form is located on chromosome 1. The product of this gene is a membrane-bound glycosylated enzyme that is expressed in a variety of tissues and is, therefore, referred to as the tissue-nonspecific form of the enzyme. A proposed function of this form of the enzyme is in regulating matrix mineralization through its ability to degrade mineralization-inhibiting pyrophosphate. Mice that lack a functional form of this enzyme (gene knockout mice) show abnormal skeletal and dental development including a mineralization deficiency called osteomalacia/odontomalacia (hypomineralization of bones and teeth). ^{[7] [8] [9] [10]} Humans with inactivating mutations in the ALPL gene likewise have variable degrees of mineralization defects depending on the location of the mutation in the ALPL gene. ^{[11] [12]}

Structure

Tissue Non-Specific Alkaline Phosphatase (TNAP), encoded by the ALPL gene, exhibits an intriguing octameric structure as revealed by X-ray crystallography. ^[13] This distinct arrangement consists of four individual dimeric TNAP units. Structural studies on homologs of TNAP, namely human (ALPP) ^[14] and Escherichia coli (ecPhoA), ^[15] have identified the dimer as the minimal stable unit of TNAP. Notably, a single TNAP protein contains four metal ion binding sites: two Zn²⁺ sites and one Mg²⁺ site situated in the reaction center, and one Ca2+ site within the regulatory pocket. The octameric state observed in TNAP is unique compared to previously characterized alkaline phosphatases, all of which have been found in a dimeric state.

Clinical significance

This enzyme has been linked directly to a disorder known as hypophosphatasia, a disorder that is characterized by low serum ALP and undermineralised bone (osteomalacia). The character of this disorder can vary, however, depending on the specific mutation, since this determines age of onset and severity of symptoms.

The severity of symptoms ranges from premature loss of deciduous teeth with no bone abnormalities to stillbirth ^[16] depending upon which amino acid ^{[17] [18]} is changed in the ALPL gene. Mutations in the ALPL gene lead to varying low activity of the enzyme tissue-nonspecific alkaline phosphatase (TNSALP) resulting in hypophosphatasia (HPP). ^[19] There are different clinical forms of HPP which can be inherited by an autosomal recessive trait or autosomal dominant trait, ^[16] the former causing more severe forms of the disease. Alkaline phosphatase allows for mineralization of calcium and phosphorus by bones and teeth. ^[19] ALPL gene mutation leads to insufficient TNSALP enzyme and allows for an accumulation of chemicals such as inorganic pyrophosphate ^[19] to indirectly cause elevated calcium levels in the body and lack of bone calcification.

The mutation E174K, where a glycine is converted to an alanine amino acid at the 571st position of its respective polypeptide chain, is a result of an ancestral mutation that occurred in Caucasians and shows a mild form of HPP. ^[16]

References

Further reading

External links

• GeneReviews/NCBI/NIH/UW entry on Hypophosphatasia
• Human ALPL genome location and ALPL gene details page in the UCSC Genome Browser.