A missense mutation in the human liver/bone/kidney alkaline phosphatase gene causing a lethal form of hypophosphatasia.

Abstract

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of serum and tissue liver/bone/kidney alkaline phosphatase (L/B/K ALP) activity. Clinical severity is variable, ranging from death in utero (due to severe rickets) to pathologic fractures first presenting in adult life. Affected siblings, however, are phenotypically similar. Severe forms of the disease are inherited in an autosomal recessive fashion; heterozygotes often show reduced serum ALP activity. The specific gene defects in hypophosphatasia are unknown but are thought to occur either at the L/B/K ALP locus or within another gene that regulates L/B/K ALP expression. We used the polymerase chain reaction to examine L/B/K ALP cDNA from a patient with a perinatal (lethal) form of the disease. We observed a guanine-to-adenine transition in nucleotide 711 of the cDNA that converts alanine-162 of the mature enzyme to threonine. The affected individual, whose parents are second cousins, is homozygous for the mutant allele. Introduction of this mutation into an otherwise normal cDNA by site-directed mutagenesis abolishes the expression of active enzyme, demonstrating that a defect in the L/B/K ALP gene results in hypophosphatasia and that the enzyme is, therefore, essential for normal skeletal mineralization.

Severe skeletal toxicity from protracted etidronate therapy for generalized arterial calcification of infancy

“…(19,24) HPP is the inborn error of metabolism caused by loss-offunction mutation(s) within the gene that encodes TNSALP. (52) PPi is a natural substrate for this cell-surface enzyme, (53) and consequently PPi accumulates extracellularly in HPP and leads to rickets or osteomalacia. (54,55) Elevated plasma levels of PLP in HPP reflect extracellular excesses of this TNSALP substrate.…”

Hypophosphatasia: Identification of five novel missense mutations (G507A, G705A, A748G, T1155C, G1320A) in the tissue-nonspecific alkaline phosphatase gene among Japanese patients

“…To date 12 different mutations in the TNSALP gene have been identified in patients' alleles (Weiss et al, 1988a;Henthorn et al, 1992;Greenberg et al, 1993;Orimo et al, 1994). Previously, we revealed immunological properties of serum ALP of HOPS patients and obtained useful data for the diagnosis of HOPS types (Goseki et al, 1990).…”

Outcome of Perinatal Hypophosphatasia in Manitoba Mennonites: A Retrospective Cohort Analysis

“…Both autosomal recessive and autosomal dominant forms of the disease are described. All but odontohypophosphatasia manifest defective skeletal mineralization (Fraser 1957) and involve loss-of-function mutation of the TNSALP gene (Whyte 1994) which was characterized in 1988 (Weiss et al 1988). To date, more than 260 mutations have been recorded in the TNSALP Gene Mutations Database (http:// www.sesep.uvsq.fr/03_hypo_mutations.php).…”