In fibroblasts from a girl who presented at 2 months of age with severe hypophosphatasia (241500) and died at age 8 months, Henthorn et al. (1992) identified compound heterozygosity for 2 mutations in the ALPL gene: a 747G-A transition in exon 6, resulting in a glu174-to-lys (E174K) substitution, and a 1309A-T transversion in exon 10, resulting in an asp361-to-val (D361V) substitution (171760.0009).
For discussion of the asp378-to-val (D378V) mutation found in compound heterozygous state in the ALPL gene in patients with childhood (241510) or adult (146300) hypophosphatasia by Henthorn et al. (1992), see 171760.0003.
Herasse et al. (2002) investigated whether the E174K mutation had a unique origin or multiple origins arising from de novo mutations by genotyping 3 intragenic polymorphisms in patients with E174K and unaffected related individuals. Because all of the E174K mutations were found on a common ancestral haplotype, the authors suggested that a founder mutation occurred on a single chromosome in northwestern Europe and spread by human migration.