On this page
ALPL
alkaline phosphatase, biomineralization associated
The ALPL gene provides instructions for an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP), which is crucial for the proper development and mineralisation of bones and teeth. The ALPL gene is responsible for producing the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme.
ALPL is located on the short (p) arm of chromosome 1, at band 1p36.12. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The ALPL gene encodes the enzyme tissue-nonspecific alkaline phosphatase (TNSALP), which is active in numerous tissues, particularly bone, liver, and kidneys. TNSALP is fundamental for the process where minerals like calcium and phosphorus are deposited into developing bones and teeth.
This mineralisation is critical for the formation of rigid and strong bones, as well as teeth capable of withstanding chewing forces. Disruptions in the function of the ALPL gene can lead to impaired mineralisation.
What the gene does
The tissue-nonspecific alkaline phosphatase (TNSALP) enzyme, produced from the ALPL gene, acts as a phosphatase. This means its primary function is to remove phosphate groups, which are clusters of oxygen and phosphorus atoms, from other molecules.
This enzymatic activity is essential for mineralisation, a biological process involving the deposition of minerals into tissues. Specifically, TNSALP facilitates the proper incorporation of calcium and phosphorus into the extracellular matrix of developing bones and teeth. This function ensures these structures achieve their necessary strength and rigidity. The enzyme's widespread activity underscores its importance in various bodily tissues beyond just the skeletal system.
Video: Genetics 101
Chromosome location
The ALPL gene is located on chromosome 1, specifically at band 1p36.12. This genomic position indicates its physical address within the human genome. The gene spans a significant region of this chromosome.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the ALPL gene can alter the structure and function of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. Hundreds of such variants have been identified, with many leading to a single amino acid change in the protein. Other types of variants include insertions, deletions, or changes that affect how the gene's instructions are used to build the enzyme.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1277G>C | p.Gly426Ala | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.187_205del | p.Gly63fs | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.242del | p.Pro81fs | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.250G>A | p.Glu84Lys | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.297+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.401C>A | p.Thr134Asn | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.461C>T | p.Ala154Val | Pathogenic/Likely pathogenic | ★★☆☆ | Adult hypophosphatasia |
c.472+1G>A | - | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.50C>T | p.Ser17Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.567_568insT | p.Asn190Ter | Pathogenic | ★★☆☆ | Hypophosphatasia |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the ALPL gene are the genetic basis for Hypophosphatasia. This condition is characterised by defective bone and tooth mineralisation, resulting from insufficient activity of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme.
Inheritance pattern
Conditions caused by pathogenic ALPL variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ALPL gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is listed as 'green' on multiple NHS Genomic PanelApp panels, including those for DDG2P, Early onset or syndromic epilepsy, Foetal anomalies (R21), Hypophosphataemia or rickets (R154), Likely inborn error of metabolism (R98), Osteogenesis imperfecta (R102), Rare syndromic craniosynostosis or isolated multisuture synostosis (R100), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders. This indicates strong evidence for its involvement in these conditions within a clinical diagnostic context.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ALPL gene do?
The ALPL gene provides instructions for making an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme is critical for mineralisation, the process by which minerals like calcium and phosphorus are deposited into developing bones and teeth to make them strong.
What is Hypophosphatasia?
Hypophosphatasia is an inherited condition caused by pathogenic variants in the ALPL gene. It leads to impaired bone and tooth mineralisation due to a deficiency in the TNSALP enzyme, resulting in bones that are soft and easily fractured.
How common are ALPL gene variants?
Hundreds of different variants in the ALPL gene have been identified in individuals with Hypophosphatasia. These variants can range from single amino acid changes to larger insertions or deletions within the gene.
References
- Whyte MP. Hypophosphatasia - aetiology, nosology, pathogenesis, diagnosis and treatment. Nature reviews. Endocrinology. 2016. PMID: 26893260
- Mornet E. Molecular Genetics of Hypophosphatasia and Phenotype-Genotype Correlations. Sub-cellular biochemistry. 2015. PMID: 26219705
- Whyte MP. Physiological role of alkaline phosphatase explored in hypophosphatasia. Annals of the New York Academy of Sciences. 2010. PMID: 20392236
- Spentchian M, Brun-Heath I, Taillandier A. Characterization of missense mutations and large deletions in the ALPL gene by sequencing and quantitative multiplex PCR of short fragments. Genetic testing. 2006. PMID: 17253930
- Brun-Heath I, Taillandier A, Serre JL. Characterization of 11 novel mutations in the tissue non-specific alkaline phosphatase gene responsible for hypophosphatasia and genotype-phenotype correlations. Molecular genetics and metabolism. 2005. PMID: 15694177
- Spentchian M, Merrien Y, Herasse M. Severe hypophosphatasia: characterization of fifteen novel mutations in the ALPL gene. Human mutation. 2003. PMID: 12815606
- Mornet E, Stura E, Lia-Baldini AS. Structural evidence for a functional role of human tissue nonspecific alkaline phosphatase in bone mineralization. The Journal of biological chemistry. 2001. PMID: 11395499
- Mornet E. Hypophosphatasia: the mutations in the tissue-nonspecific alkaline phosphatase gene. Human mutation. 2000. PMID: 10737975
- Whyte MP. Hypophosphatasia and the role of alkaline phosphatase in skeletal mineralization. Endocrine reviews. 1994. PMID: 7988481