Identification of novel missense mutations (Phe310Leu and Gly439Arg) in a neonatal case of hypophosphatasia

J Clin Endocrinol Metab. 1996 Dec;81(12):4458-61. doi: 10.1210/jcem.81.12.8954059.


Hypophosphatasia is associated with a defect of the tissue-non-specific alkaline phosphatase gene. We performed a mutational analysis in a surviving patient diagnosed at birth as having hypophosphatasia, on the basis of a low level of serum alkaline phosphatase (ALP) activity and characteristic radiographical findings. She had two sisters, one of whom died of respiratory failure complicated by perinatal hypophosphatasia; the other seemed healthy, with a relatively low activity level of ALP. The patient's parents also had low ALP activity. Sequence analysis of the tissue-nonspecific alkaline phosphatase gene was performed, using genomic DNA and total RNA from the skin fibroblasts of the patient and the peripheral mononuclear cells of her parents. The conversion of Phe to Leu at codon 310 (F310L) and Gly to Arg at 439 (G439R) were identified in the patient. Interestingly, the reconstructive experiments demonstrated that the F310L mutant exhibited an ALP activity level 65% of the normal level, whereas the mutant G439R had no activity. Moreover, the digestion by StuI, after a PCR using complementary DNA extracted from fibroblasts of the patient and lymphocytes of her father, revealed a relatively low messenger RNA level of F310L. These findings suggest that the neonatal case of hypophosphatasia was associated with compound mutations, one of which caused the loss of ALP activity and the other of which caused a slight reduction of the ALP activity, with a relatively low level of messenger RNA.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Alkaline Phosphatase / blood
  • Alkaline Phosphatase / genetics
  • DNA, Complementary / analysis
  • Female
  • Humans
  • Hypophosphatasia / genetics*
  • Infant, Newborn
  • Male
  • Mutation*
  • Polymorphism, Genetic
  • Pregnancy


  • DNA, Complementary
  • Alkaline Phosphatase