First identification of a gene defect for hypophosphatasia: Evidence that alkaline phosphatase acts in skeletal mineralization

Mitchell J. Weiss, David E.C. Cole, Kunal Ray, Michael P. Whyte, Mary Ann Laferty, Richard Mulivor, Harry Harris

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Hypophosphatasia is a heritable disorder characteriazed by defective osteogenesis and deficient liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Severe forms of the disease are inherited in an autosomal recessive fashion. We examined cultured skin fibroblasts from twelve patients with severe hypophosphatasia. All were deficient in L/B.K ALP activity, yet produced normal levels of the corresponding mRNA. Sequence analysis of L/B/K ALP cDNA isolated from one of the patient-derived fibroblast lines revealed a point mutation that converted amino acid 162 of mature L/B/K ALP from alanine to threonine. The patient was homozygous and the parents, who are second cousins, heterozygous for this mutation. Introduction of the mutation into an otherwise normal cDNA disrupted the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene resulted in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization.

Original languageEnglish
Pages (from-to)99-106
Number of pages8
JournalConnective Tissue Research
Volume21
Issue number1-4
DOIs
StatePublished - 1989

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