ALPL

ALPL is the gene that encodes tissue-nonspecific alkaline phosphatase (TNSALP), a dimeric enzyme of the alkaline phosphatase family. In humans, the ALPL gene is located on chromosome 1p36.12 and is expressed in multiple tissues, including bone, liver, kidney, and central nervous system. The enzyme is typically attached to the outer cell membrane via a glycosylphosphatidylinositol (GPI) anchor and requires divalent metal ions, such as zinc and magnesium, for catalysis. Its activity has an alkaline pH optimum.

Function and biology: ALPL/TNSALP dephosphorylates a wide range of phosphate esters, contributing to the hydrolysis of inorganic pyrophosphate (PPi) and other substrates. By reducing PPi levels, ALPL promotes mineralization of the extracellular matrix, a process essential for proper bone and tooth mineralization. The enzyme also participates in various phosphate metabolism pathways and can influence levels of phosphorylated vitamin B6 (pyridoxal 5′-phosphate, or PLP) in body fluids.

Clinical significance: Mutations in ALPL cause hypophosphatasia, a rare inherited disorder with a spectrum of severity from lethal perinatal forms to milder, later-onset conditions. Features include defective bone mineralization, rickets-like deformities, skeletal abnormalities, and dental problems such as premature tooth loss due to cementum defects. Laboratory findings often show low serum alkaline phosphatase activity and elevated levels of ALPL substrates such as PLP.

Diagnosis and treatment: Genetic testing can identify pathogenic ALPL variants. Serum ALP activity is used as a biochemical marker; low activity alongside elevated PLP supports hypophosphatasia. Treatment includes enzyme-replacement therapy with asfotase alfa, a recombinant TNSALP, which targets bone and other affected tissues. Supportive care and management of skeletal and dental complications are also important.