Aberrant properties of alkaline phosphatase in patient fibroblasts correlate with clinical expressivity in severe forms of hypophosphatasia

The markedly variable clinical expressivity of hypophosphatasia was explored by examining biochemical properties of alkaline phosphatase (ALP) in fibroblasts cultured from 16 patients with severe autosomal recessive forms of this metabolic bone disease. Outcome ranged from death in utero to survival into childhood. Mean ALP activity in patients was 4.3% of controls. Gel filtration analysis indicated a mixture of dimeric and tetrameric ALP in both subject groups. Control cells produced levels of bone ALP cross-reacting material that correlated strongly with ALP activity. Patient bone ALP cross- reacting material levels averaged 41% of the control mean with a wide range of individual values that did not correlate with ALP activity. Control ALP activity was stable in 3% SDS and during electrodialysis. Patient ALP activity was generally unstable under both conditions but with a considerable range of individual values. Fibroblast ALP from every patient exhibited some aberrancy in physicochemical and immunoreactive properties. These data strongly correlated (r = 0.95) with clinical severity. There appeared to be specific associations of tissue nonspecific (bone/liver/kidney isoenzyme) ALP (TNSALP) gene mutations with aberrant enzyme properties and disease severity. We conclude that a spectrum of aberrant biochemical properties of the TNSALP enzyme, caused by different combinations of TNSALP gene missense mutations, reflects the variable clinical expressivity of hypophosphatasia.