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Titolo:
A molecular approach to dominance in hypophosphatasia
Autore:
Lia-Baldini, AS; Muller, F; Taillandier, A; Gibrat, JF; Mouchard, M; Robin, B; Simon-Bouy, B; Serre, JL; Aylsworth, AS; Bieth, E; Delanote, S; Freisinger, P; Hu, JCC; Krohn, HP; Nunes, ME; Mornet, E;
Indirizzi:
Univ Versailles, Lab Cytogenet & Genet Mol Humaine, F-78035 Versailles, France Univ Versailles Versailles France F-78035 ne, F-78035 Versailles, France Univ Versailles, Ctr Etud Biol Prenatale, SESEP, F-78000 Versailles, France Univ Versailles Versailles France F-78000 EP, F-78000 Versailles, France Inst Natl Rech Agr, Unite Bioinformat, Versailles, France Inst Natl Rech Agr Versailles France te Bioinformat, Versailles, France Univ N Carolina, Dept Pediat & Genet, Chapel Hill, NC USA Univ N CarolinaChapel Hill NC USA t Pediat & Genet, Chapel Hill, NC USA CHU Purpan, Serv Genet, Toulouse, France CHU Purpan Toulouse FranceCHU Purpan, Serv Genet, Toulouse, France Univ Hosp, Dept Gynecol, Ghent, Belgium Univ Hosp Ghent BelgiumUniv Hosp, Dept Gynecol, Ghent, Belgium Tech Univ Munich, Kinderklin, D-8000 Munich, Germany Tech Univ Munich Munich Germany D-8000 inderklin, D-8000 Munich, Germany Univ Texas, Hlth Sci Ctr, Dept Pediat Dent, San Antonio, TX 78284 USA UnivTexas San Antonio TX USA 78284 ediat Dent, San Antonio, TX 78284 USA Reinhardt Nieter Krankenhaus, Wilhelmshaven, Germany Reinhardt Nieter Krankenhaus Wilhelmshaven Germany lhelmshaven, Germany USAF, Ctr Genet Med, Keesler AFB, MS USA USAF Keesler AFB MS USAUSAF, Ctr Genet Med, Keesler AFB, MS USA
Titolo Testata:
HUMAN GENETICS
fascicolo: 1, volume: 109, anno: 2001,
pagine: 99 - 108
SICI:
0340-6717(200107)109:1<99:AMATDI>2.0.ZU;2-B
Fonte:
ISI
Lingua:
ENG
Soggetto:
NONSPECIFIC ALKALINE-PHOSPHATASE; INFANTILE HYPOPHOSPHATASIA; ADULT HYPOPHOSPHATASIA; MISSENSE MUTATIONS; GENE; PATIENT; IDENTIFICATION; FAMILY; FORMS; MILD;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Life Sciences
Citazioni:
37
Recensione:
Indirizzi per estratti:
Indirizzo: Mornet, E Univ Versailles, Lab Cytogenet & Genet Mol Humaine, Batiment Fermat,45 AveEtats Unis, F-78035 Versailles, France Univ Versailles Batiment Fermat,45 Ave Etats Unis Versailles France F-78035
Citazione:
A.S. Lia-Baldini et al., "A molecular approach to dominance in hypophosphatasia", HUM GENET, 109(1), 2001, pp. 99-108

Abstract

Hypophosphatasia is an inherited disorder characterized by defective bone mineralization and a deficiency of tissue-nonspecific alkaline phosphatase (TNSALP) activity. The disease is highly variable in its clinical expression, because of various mutations in the TNSALP gene. In approximately 14% ofthe patients tested in our laboratory, only one TNSALP gene mutation was found, despite exhaustive sequencing of the gene, suggesting that missing mutations are harbored in intron or regulatory sequences or that the disease is dominantly transmitted. The distinction between these two situations is of importance, especially in terms of genetic counseling, but dominance is sometimes difficult to conclusively determine by using familial analysis since expression of the disease may be highly variable, with parents of even severely affected children showing no or extremely mild symptoms of the disease. We report here the study of eight point mutations (G46 V, A99T, S164L, R167 W, R206 W, G232 V, N461I, 1473F) found in patients with no other detectable mutation. Three of these mutations, G46 V, S164L, and 1473F, have not previously been described. Pedigree and/or serum alkaline phosphatase data suggested possible dominant transmission in families with A99T, R167 W, and G232 V. By means of site-directed mutagenesis, transfections in COS-1 cells, and three-dimensional (3D) modeling, we evaluated the possible dominant effect of these eight mutations. The results showed that four of these mutations (G46 V, A99T, R167 W, and N461I) exhibited a negative dominant effect by inhibiting the enzymatic activity of the heterodimer, whereas the four others did not show such inhibition. Strong inhibition resulted in severe hypophosphatasia, whereas partial inhibition resulted in milder forms of the disease. Analysis of the 3D model of the enzyme showed that mutations exhibiting a dominant effect were clustered in two regions, viz., the activesite and an area probably interacting with a region having a particular biological function such as dimerization, tetramerization, or membrane anchoring.

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Documento generato il 14/07/20 alle ore 03:40:38