Perinatal hypophosphatasia: Radiology, pathology and molecular biology studies in a family harboring a splicing mutation (648+1A) and a novel missense mutation (N400S) in the tissue-nonspecific alkaline phosphatase (TNSALP) gene

We report on a postmortem diagnosis of perinatal lethal hypophosphatasia, a n inborn error of metabolism characterized by a liver/bone/kidney alkaline phosphatase (ALP)-related defective bone mineralization due to mutations in the tissue-nonspecific alkaline phosphatase (TNSALP) gene. Radiological an d pathological studies identified a perinatal lethal hypophosphatasia showi ng a generalized bone mineralization defect including asymmetry of the cerv ical vertebral arches in a 22 +4 weeks' gestation fetus. Both parents revea led low serum ALP activities supporting the diagnosis. Sequencing analysis of the TNSALP gene showed two heterozygous mutations, 648+1A, a mutation af fecting the donor splice site in exon 6, and N400S, a novel missense mutati on in exon 11, located near the active site and very close to histidins 364 and 437, two crucial residues of the active site. Sequencing of exons 6 an d 11 in the parents showed that 648+1A was from maternal origin and N400S f rom paternal origin. DNA-based prenatal testing in the subsequent pregnancy following a chorionic villous sampling performed at 10 weeks of gestation showed no mutation and a healthy infant was born at term. (C) 2001 Wiley-Li ss, Inc.