Functional characterization of a novel mutation localized in the start codon of the tissue-nonspecific alkaline phosphatase gene.

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 -