A Missense Mutation in the Human Liver/Bone/Kidney Alkaline Phosphatase Gene Causing a Lethal Form of Hypophosphatasia

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...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 1988-10, Vol.85 (20), p.7666-7669
Main Authors: Weiss, Mitchell J., David E. C. Cole, Ray, Kunal, Whyte, Michael P., Lafferty, Mary Ann, Mulivor, Richard A., Harris, Harry
Format: Article
Language:English
Subjects:
550401 - Genetics- Tracer Techniques
ALANINES
ALKALINE PHOSPHATASE
Alkaline Phosphatase - deficiency
Alkaline Phosphatase - genetics
Alleles
AMINO ACIDS
ANIMALS
BASIC BIOLOGICAL SCIENCES
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
BIOCHEMISTRY
Biological and medical sciences
BODY
Bone and Bones - enzymology
Bones
CARBOXYLIC ACIDS
CHEMISTRY
Classical genetics, quantitative genetics, hybrids
Complementary DNA
DAYS LIVING RADIOISOTOPES
DIGESTIVE SYSTEM
DISEASES
DNA
DNA - genetics
DNA SEQUENCING
ENZYMES
ESTERASES
Fibroblasts
Fundamental and applied biological sciences. Psychology
GENE MUTATIONS
Genetic mutation
Genetics of eukaryotes. Biological and molecular evolution
GLANDS
HEREDITARY DISEASES
Homozygote
Human
Humans
HYBRIDIZATION
HYDROLASES
HYDROXY ACIDS
Hypophosphatasia
Hypophosphatasia - enzymology
Hypophosphatasia - genetics
ISOTOPES
Kidney - enzymology
KIDNEYS
LIGHT NUCLEI
LIVER
Liver - enzymology
MAMMALS
MAN
Medical sciences
Messenger RNA
Metabolic diseases
Metals (hemochromatosis...)
MINERALIZATION
Mutation
MUTATIONS
NUCLEI
Nucleic Acid Hybridization
NUCLEIC ACIDS
ODD-ODD NUCLEI
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
Other metabolic disorders
Pedigree
PHOSPHATASES
PHOSPHORUS 32
PHOSPHORUS ISOTOPES
Plasmids
PRIMATES
RADIOISOTOPES
RECOMBINANT DNA
SKELETON
STRUCTURAL CHEMICAL ANALYSIS
THREONINE
VERTEBRATES
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Description
Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.85.20.7666