ALPI Gene

The ALPI gene (ALPI stands for "alkaline phosphatase, intestinal") is a protein-coding gene located on chromosome 2q37.1.

There are at least four different but related alkaline phosphatases (AP):

• Intestinal IAP
• Placental AP
• Placental AP and
• Liver/bone/kidney (tissue nonspecific) AP.

The ALPI gene encodes intestinal alkaline phosphatase, a brush border metalloenzyme that hydrolyzes phosphate from the lipid A portion of lipopolysaccharides, thereby dramatically reducing the agonist activity of Toll-like receptor 4. Intestinal alkaline phosphatase is an essential component of the intestinal mucosal defense system and is thought to have a function of preventing bacterial translocation in the gut (Duclaux-Loras R et al. 2018).

Intestinal alkaline phosphatase (IAP) is a multifunctional protein that has been shown to primarily protect the intestine. The role of IAP in maintaining intestinal homeostasis is underscored by the observation that IAP expression is impaired in many gastrointestinal diseases such as inflammatory bowel disease (IBD), necrotizing enterocolitis, and metabolic syndrome, and that exogenous IAP supplementation improves outcomes associated with these conditions (Singh SB et al.2021).

Innate immune functions of IAP include lipopolysaccharide (LPS) detoxification, protection of intestinal barrier integrity, regulation of the gut microbiome, and its anti-inflammatory effects. A recently discovered novel function of IAP is the induction of autophagy. Because of its critical role in gut physiology and excellent safety profile, IAP is being used in Phase 2a clinical trials to treat diseases such as sepsis-associated acute kidney injury.

ALPI mutations impaired either the stability or catalytic activity of ALPI, rendering the enzyme incapable of detoxifying lipopolysaccharide-dependent signal transduction. The consequences are inflammatory bowel disease (IBD).

A biallelic inherited mutation in ALPI has been shown to be a Mendelian cause of inflammatory bowel disease.

Diseases associated with ALPI include hypophosphatasia and adenoid cystic carcinoma of the trachea.

Hypophosphatasia is an inherited disorder that affects the development of bones and teeth. This disorder interferes with the mineralization of bones and teeth. The signs and symptoms of hypophosphatasia vary widely and can occur from before birth into adulthood. The most severe forms of the disorder usually occur before birth and in early childhood. Hypophosphatasia weakens and softens bones, resulting in skeletal abnormalities similar to another childhood bone disorder, rickets.

These results suggest that ALPI mutations should be included in screening for monogenic causes of inflammatory bowel disease. They lay the foundation for ALPI-based treatments in inflammatory bowel disease (Duclaux-Loras R et al. 2018).

1. Duclaux-Loras R et al. (2018) Human ALPI deficiency causes inflammatory bowel disease and highlights a key mechanism of gut homeostasis. EMBO Mol Med 10:e8483.
2. Hu JC et al (2000) Characterization of a family with dominant hypophosphatasia. Europ J Oral Sci 108: 189-194.
3. Kishnani PS et al. (2021) Investigation of ALPL variant states and clinical outcomes: an analysis of adults and adolescents with hypophosphatasia treated with asfotase alfa. Molec Genet Metab 133: 113-121.
4. Singh SB et al.(2021) Role of Intestinal Alkaline Phosphatase in Innate Immunity. Biomolecules 11:1784.
5. Yang Y et al. (2015) Intestinal alkaline phosphatase deficiency leads to lipopolysaccharide desensitization and faster weight gain. Infect Immun 83:247-258.