A homoallelic Gly317-->Asp mutation in ALPL causes the perinatal (lethal) form of hypophosphatasia in Canadian mennonites.
We have discovered a single homoallelic nucleotide substitution as the putative cause of the perinatal (lethal) form of hypophosphatasia in Canadian Mennonites. Previous linkage and haplotype analysis in this population suggested that a single mutational event was responsible for this autosomal recessive form of hypophosphatasia. The mutation is a guanosine-to-adenosine substitution at nucleotide position 1177 in exon 10 of the tissue nonspecific (liver/bone/kidney) alkaline phosphatase gene. This Gly317-->Asp mutation segregates exclusively with the heterozygote phenotype we previously assigned by biochemical testing (maximum combined lod score of 18.24 at theta = 0.00). This putative disease-causing mutation has not been described in controls nor in other non-Mennonite probands with both lethal and nonlethal forms of hypophosphatasia studied to date. This Gly317-->Asp mutation changes a polar glycine to an acidic aspartate at amino acid position 317 within the highly conserved active site region of the 507-amino-acid polypeptide. Carrier screening for this lethal mutation in our high-risk population is now feasible.
Greenberg
C R
CR
Department of Pediatrics, University of Manitoba, Winnipeg, Canada.
Taylor
C L
CL
Haworth
J C
JC
Seargeant
L E
LE
Philipps
S
S
Triggs-Raine
B
B
Chodirker
B N
BN
D000469:Alkaline Phosphatase / Q000172:deficiency / Q000235:genetics*; D000483:Alleles; D001483:Base Sequence; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D018076:DNA, Complementary / Q000235:genetics; D005006:Ethnicity / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D005796:Genes; D005804:Genes, Lethal; D005808:Genes, Recessive; D006239:Haplotypes / Q000235:genetics; D006579:Heterozygote; D006801:Humans; D007014:Hypophosphatasia / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D007231:Infant, Newborn; D007527:Isoenzymes / Q000172:deficiency / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008350:Manitoba / Q000453:epidemiology; D008969:Molecular Sequence Data; D009864:Ontario / Q000453:epidemiology; D017354:Point Mutation
D018076:DNA, Complementary; D007527:Isoenzymes; D000469:Alkaline Phosphatase