Kn. Fedde et al., ABERRANT PROPERTIES OF ALKALINE-PHOSPHATASE IN PATIENT FIBROBLASTS CORRELATE WITH CLINICAL EXPRESSIVITY IN SEVERE FORMS OF HYPOPHOSPHATASIA, The Journal of clinical endocrinology and metabolism, 81(7), 1996, pp. 2587-2594
The markedly variable clinical expressivity of hypophosphatasia was ex
plored by examining biochemical properties of alkaline phosphatase (AL
P) in fibroblasts cultured from 16 patients with severe autosomal rece
ssive 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 dime
ric and tetrameric ALP in both subject groups. Control cells produced
levels of bone ALP cross-reacting material that correlated strongly wi
th ALP activity. Patient bone ALP cross-reacting material levels avera
ged 41% of the control mean with a wide range of individual values tha
t did not correlate with ALP activity. Control ALP activity was stable
in 3% SDS and during electrodialysis. Patient ALP activity was genera
lly unstable under both conditions but with a considerable range of in
dividual values. Fibroblast ALP from every patient exhibited some aber
rancy in physicochemical and immunoreactive properties. These data str
ongly correlated (r = 0.95) with clinical severity. There appeared to
be specific associations of tissue nonspecific (bone/liver/kidney isoe
nzyme) 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 express
ivity of hypophosphatasia.