Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene.
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Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene. / Mentrup, B; Marschall, C; Barvencik, Florian; Amling, Michael; Plendl, H; Jakob, F; Beck, C.
in: BONE, Jahrgang 48, Nr. 6, 6, 2011, S. 1401-1408.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene.
AU - Mentrup, B
AU - Marschall, C
AU - Barvencik, Florian
AU - Amling, Michael
AU - Plendl, H
AU - Jakob, F
AU - Beck, C
PY - 2011
Y1 - 2011
N2 - Hypophosphatasia (HPP) is a rare inborn disease caused by different mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Previous studies showed that gene mutations could exhibit a dominant negative effect leading to a mild HPP phenotype in heterozygous carriers. In the present report we describe the clinical and functional studies of a novel mutation localized in the start codon of transcript variant 1 of the ALPL gene from a female adult heterozygous carrier. The mutation results in translation of an N-terminally truncated protein, which might be identical to the deduced protein from ALPL transcript variant 2. When overexpressed in HEK-293 cells it does not exhibit any enzymatic activity and has no significant effect on the wild type ALPL protein. Furthermore it is not attached to the cell membrane. Due to the loss of the signal peptide an intracellular misrouting and a premature degradation is obvious. Hence the new isoform deposited in the database does not produce an active protein as it is the case in the natural mutation of our patient. Since the mutation does not produce a dominant negative protein in heterozygous carriers, the clinical phenotype in our patient and her relatives is very mild with only unspecific myalgia. However the patient developed bone marrow edema of both femoral heads during lactation after delivery of a healthy child, indicating a risk to develop alterations of bone metabolism in challenge situations. Her sister complains of identical symptoms, her father shows distinct symptoms of odonto-hypophosphatasia. The question if or if not carriers of ALPL mutations in general or only with distinct genotypes can be symptomatic in normal life or in challenge situations requires systematic clinical studies.
AB - Hypophosphatasia (HPP) is a rare inborn disease caused by different mutations in the tissue-nonspecific alkaline phosphatase (ALPL) gene. Previous studies showed that gene mutations could exhibit a dominant negative effect leading to a mild HPP phenotype in heterozygous carriers. In the present report we describe the clinical and functional studies of a novel mutation localized in the start codon of transcript variant 1 of the ALPL gene from a female adult heterozygous carrier. The mutation results in translation of an N-terminally truncated protein, which might be identical to the deduced protein from ALPL transcript variant 2. When overexpressed in HEK-293 cells it does not exhibit any enzymatic activity and has no significant effect on the wild type ALPL protein. Furthermore it is not attached to the cell membrane. Due to the loss of the signal peptide an intracellular misrouting and a premature degradation is obvious. Hence the new isoform deposited in the database does not produce an active protein as it is the case in the natural mutation of our patient. Since the mutation does not produce a dominant negative protein in heterozygous carriers, the clinical phenotype in our patient and her relatives is very mild with only unspecific myalgia. However the patient developed bone marrow edema of both femoral heads during lactation after delivery of a healthy child, indicating a risk to develop alterations of bone metabolism in challenge situations. Her sister complains of identical symptoms, her father shows distinct symptoms of odonto-hypophosphatasia. The question if or if not carriers of ALPL mutations in general or only with distinct genotypes can be symptomatic in normal life or in challenge situations requires systematic clinical studies.
KW - Adult
KW - Humans
KW - Female
KW - Base Sequence
KW - Heterozygote
KW - Blotting, Western
KW - Cell Line
KW - Mutagenesis, Site-Directed
KW - DNA Primers
KW - Mutation
KW - Alkaline Phosphatase/genetics
KW - Codon, Initiator
KW - Hypophosphatasia/genetics
KW - Subcellular Fractions/enzymology
KW - Adult
KW - Humans
KW - Female
KW - Base Sequence
KW - Heterozygote
KW - Blotting, Western
KW - Cell Line
KW - Mutagenesis, Site-Directed
KW - DNA Primers
KW - Mutation
KW - Alkaline Phosphatase/genetics
KW - Codon, Initiator
KW - Hypophosphatasia/genetics
KW - Subcellular Fractions/enzymology
M3 - SCORING: Journal article
VL - 48
SP - 1401
EP - 1408
JO - BONE
JF - BONE
SN - 8756-3282
IS - 6
M1 - 6
ER -