ABSTRACT
In humans, low peak bone mass is a significant risk factor for osteoporosis. We report that LRP5, encoding the low-density lipoprotein receptor-related protein 5, affects bone mass accrual during growth. Mutations in LRP5 cause the autosomal recessive disorder osteoporosis-pseudoglioma syndrome (OPPG). We find that OPPG carriers have reduced bone mass when compared to age- and gender-matched controls. We demonstrate LRP5 expression by osteoblasts in situ and show that LRP5 can transduce Wnt signaling in vitro via the canonical pathway. We further show that a mutant-secreted form of LRP5 can reduce bone thickness in mouse calvarial explant cultures. These data indicate that Wnt-mediated signaling via LRP5 affects bone accrual during growth and is important for the establishment of peak bone mass.
Subject(s)
Bone Density/genetics , Eye Abnormalities/genetics , Eye/embryology , Osteoblasts/metabolism , Osteoporosis/genetics , Receptors, LDL/physiology , Transforming Growth Factor beta , Zebrafish Proteins , Adaptor Proteins, Signal Transducing , Adult , Animals , Animals, Outbred Strains , Bone Morphogenetic Protein 2 , Bone Morphogenetic Proteins/pharmacology , COS Cells , Child , Child, Preschool , Chlorocebus aethiops , Chromosomes, Human, Pair 11/genetics , Culture Media, Conditioned/pharmacology , DNA, Complementary/genetics , Dishevelled Proteins , Female , Genes, Recessive , Heterozygote , Humans , LDL-Receptor Related Proteins , Low Density Lipoprotein Receptor-Related Protein-5 , Male , Mesoderm/cytology , Mice , Mice, Inbred C57BL , Organ Culture Techniques , Phosphoproteins/genetics , Phosphoproteins/physiology , Proteins/genetics , Proteins/physiology , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/physiology , Receptors, LDL/deficiency , Receptors, LDL/genetics , Recombinant Fusion Proteins/physiology , Recombinant Proteins , Signal Transduction , Skull/cytology , Species Specificity , Stromal Cells/cytology , Stromal Cells/drug effects , Syndrome , Transfection , Wnt Proteins , Wnt-5a Protein , Wnt2 Protein , Wnt3 Protein , Wnt4 ProteinABSTRACT
Molybdenum cofactor deficiency was diagnosed in a 3-month-old girl who presented with microcephaly, developmental delay, severe irritability, and lactic acidosis. Dietary methionine restriction, with cysteine supplementation, was associated with moderate short-term clinical improvement, including a resumption in predicted head growth, modest developmental progress, and a reduction in irritability. Clinical relapse was associated with noncompliance of dietary therapy 2 months later. Urinary sulfite levels measured by commercial dipsticks were useful in following therapy. Molybdenum cofactor deficiency is probably frequently underdiagnosed due to the lack of specific clinical or laboratory features. Screening of infants at risk for the presence of urinary sulfites or serum hypouricemia, or both, is both rapid and inexpensive.