PMID- 10332035
OWN - NLM
STAT- MEDLINE
DCOM- 19990708
LR  - 20190513
IS  - 0964-6906 (Print)
IS  - 0964-6906 (Linking)
VI  - 8
IP  - 6
DP  - 1999 Jun
TI  - Correlations of genotype and phenotype in hypophosphatasia.
PG  - 1039-46
AB  - Hypophosphatasia, a rare inherited disorder characterized by defective bone
      mineralization, is highly variable in its clinical expression. The disease is due
      to various mutations in the tissue-non-specific alkaline phosphatase ( TNSALP )
      gene. We report here the use of clinical data, site-directed mutagenesis and
      computer-assisted modelling to propose a classification of 32 TNSALP gene
      mutations found in 23 European patients, 17 affected with lethal hypophosphatasia
      and six with non-lethal hypophosphatasia. Transfection studies of the missense
      mutations found in non-lethal hypophosphatasia showed that six of them allowed
      significant residual in vitro enzymatic activity, suggesting that these mutations
      corresponded to moderate alleles. Each of the six patients with non-lethal
      hypophosphatasia carried at least one of these alleles. The three-dimensional
      model study showed that moderate mutations were not found in the active site, and
      that most of the severe missense mutations were localized in crucial domains such
      as the active site, the vicinity of the active site and homodimer interface. Some
      mutations appeared to be organized in clusters on the surface of the molecule
      that may represent possible candidates for regions interacting with the
      C-terminal end involved in glycosylphosphatidylinositol (GPI) attachment or with 
      other dimers to form tetramers. Finally, our results show a good correlation
      between clinical forms of the disease, mutagenesis experiments and the
      three-dimensional structure study, and allowed us to clearly distinguish moderate
      alleles from severe alleles. They also confirm that the extremely high phenotypic
      heterogeneity observed in patients with hypophosphatasia was due mainly to
      variable residual enzymatic activities allowed by missense mutations found in the
      human TNSALP gene.
FAU - Zurutuza, L
AU  - Zurutuza L
AD  - Centre d'Etude de Biologie Prenatale--SESEP, Universite de Versailles-Saint
      Quentin, Versailles, France.
FAU - Muller, F
AU  - Muller F
FAU - Gibrat, J F
AU  - Gibrat JF
FAU - Taillandier, A
AU  - Taillandier A
FAU - Simon-Bouy, B
AU  - Simon-Bouy B
FAU - Serre, J L
AU  - Serre JL
FAU - Mornet, E
AU  - Mornet E
LA  - eng
PT  - Journal Article
PL  - England
TA  - Hum Mol Genet
JT  - Human molecular genetics
JID - 9208958
RN  - 0 (DNA, Complementary)
RN  - EC 3.1.3.1 (Alkaline Phosphatase)
SB  - IM
MH  - Alkaline Phosphatase/chemistry/*genetics
MH  - Alleles
MH  - Amino Acid Substitution
MH  - Animals
MH  - Binding Sites/genetics
MH  - Cell Line
MH  - Child
MH  - Child, Preschool
MH  - DNA, Complementary/genetics
MH  - Dimerization
MH  - Genotype
MH  - Humans
MH  - Hypophosphatasia/enzymology/*genetics/pathology
MH  - Infant
MH  - Models, Molecular
MH  - Mutagenesis, Site-Directed
MH  - Mutation
MH  - Mutation, Missense
MH  - Phenotype
MH  - Plasmids
MH  - Protein Structure, Tertiary
MH  - Transfection
EDAT- 1999/05/20 00:00
MHDA- 1999/05/20 00:01
CRDT- 1999/05/20 00:00
PHST- 1999/05/20 00:00 [pubmed]
PHST- 1999/05/20 00:01 [medline]
PHST- 1999/05/20 00:00 [entrez]
AID - ddc115 [pii]
AID - 10.1093/hmg/8.6.1039 [doi]
PST - ppublish
SO  - Hum Mol Genet. 1999 Jun;8(6):1039-46. doi: 10.1093/hmg/8.6.1039.