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ALPL
alkaline phosphatase, biomineralization associated
The ALPL gene provides instructions for an enzyme crucial for bone and tooth mineralisation, and variants in this gene are associated with Hypophosphatasia. The ALPL gene is responsible for producing tissue-nonspecific alkaline phosphatase (TNSALP), an enzyme vital for the proper development and strength of bones and teeth.
ALPL is located on the short (p) arm of chromosome 1, at band 1p36.12. Arm ratio per GRCh38 - banding schematic.
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Overview
The ALPL gene encodes the enzyme tissue-nonspecific alkaline phosphatase (TNSALP), which is broadly active in various tissues including the liver, kidneys, and importantly, in bones and teeth. This enzyme is fundamental for skeletal mineralisation, a process where minerals such as calcium and phosphorus are deposited to form strong and rigid bones and teeth [PMID:28770281].
Dysfunction of the ALPL gene is linked to Hypophosphatasia, an inherited disorder characterised by defective bone and tooth mineralisation. Understanding the ALPL gene and its protein's function is therefore key to comprehending the biological basis of skeletal health.
What the gene does
The protein encoded by the ALPL gene, tissue-nonspecific alkaline phosphatase (TNSALP), acts as a phosphatase. This means its primary role is to remove phosphate groups, which are clusters of oxygen and phosphorus atoms, from various molecules [PMID:28770281]. This enzymatic activity is essential for the mineralisation process in bones and teeth.
During mineralisation, TNSALP helps to regulate the local concentrations of phosphate and pyrophosphate, which are critical for the controlled deposition of calcium and phosphorus into developing skeletal structures. Properly mineralised bones are strong and rigid, while adequately mineralised teeth can withstand the stresses of chewing and grinding [PMID:28770281]. Therefore, TNSALP's catalytic action directly impacts the structural integrity and function of the human skeleton.
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Chromosome location
The ALPL gene is located on chromosome 1, specifically at position 1p36.12. This region represents a specific segment on the short (p) arm of chromosome 1. The gene provides instructions for a protein composed of 524 amino acids.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ALPL gene can affect the production or function of the tissue-nonspecific alkaline phosphatase (TNSALP) enzyme. Over 300 different genetic changes in the ALPL gene have been identified that are associated with related health conditions. These variants often involve a single amino acid change in the enzyme, but can also include insertions, deletions, or alterations in how the gene's instructions are processed.
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/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.297+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.472+1G>A | - | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.50C>T | p.Ser17Phe | Pathogenic/Likely pathogenic | ★★☆☆ | Hypophosphatasia |
c.567_568insT | p.Asn190Ter | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.862+1G>C | - | Pathogenic | ★★☆☆ | Hypophosphatasia |
c.928dup | p.Ser310fs | Pathogenic/Likely 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
Variants in the ALPL gene are primarily associated with Hypophosphatasia (AR), an inherited metabolic bone disorder. This condition arises when the tissue-nonspecific alkaline phosphatase enzyme is deficient or dysfunctional, leading to impaired mineralisation of bones and teeth. The severity of Hypophosphatasia can vary widely, ranging from severe forms that are apparent in infancy to milder forms that may present later in life.
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 within the NHS Genomic Medicine Service due to its clinical significance. It is included in several Green RAG status panels in PanelApp, indicating strong evidence for its association with specific conditions. These panels include 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.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ALPL gene?
The ALPL gene provides instructions for an enzyme called tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme is crucial for the mineralisation of bones and teeth, a process that makes them strong and rigid.
What condition is associated with ALPL gene variants?
Variants in the ALPL gene are primarily associated with Hypophosphatasia, an inherited disorder characterised by defective mineralisation of bones and teeth due to insufficient or faulty TNSALP enzyme activity.
How common are ALPL gene variants?
Over 300 different genetic changes have been identified in the ALPL gene that are linked to Hypophosphatasia. These variants can affect the enzyme's function in various ways, leading to a spectrum of clinical severity.
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