FAQ: What Role Does Tissue-Nonspecific Alkaline Phosphatase (TNSALP) Play in HPP?

In this educational FAQ, Heather Mambretti, PA-C, a rheumatology physician assistant and RhAPP faculty and board member, explains the critical role of tissue-nonspecific alkaline phosphatase (TNSALP) in hypophosphatasia (HPP). TNSALP is an essential enzyme involved in bone and tooth mineralization, as well as vitamin B6 transport into cells. Mutations in the ALPL gene, which encodes TNSALP, lead to reduced enzyme activity, accumulation of mineralization substrates, and defective bone formation. This video reviews how inactivating ALPL gene variants—of which more than 450 have been identified—contribute to the clinical spectrum of hypophosphatasia, including differences in autosomal recessive and autosomal dominant inheritance patterns. Severe forms such as perinatal and infantile HPP are often associated with autosomal recessive mutations, while milder presentations may follow a dominant pattern. Clinicians will gain a clear understanding of the pathophysiology of HPP, the genetic variability behind disease expression, and why bone, liver, and kidney involvement are common. For more rheumatology-focused education, visit RhAPP.org, download the RhAPP ACE App, and explore additional expert content on the Content Rheum.

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