Gene/Protein
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Enzyme
Compound
Pivot Concepts:
Gene/Protein
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Target Concepts:
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Query: UNIPROT:P43026 (
lipopolysaccharide
)
62,215
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
We report on a patient with a clinical phenotype showing all the features of the multiple synostoses syndrome or the facioaudiosymphalangism syndrome, including symphalangism, condunction deafness, and the typical facies. Previously, it was shown that this condition is genetically heterogeneous with initially mutations described in the
NOG
gene, coding for Noggin, an extracellular antagonist of bone morphogenetic proteins. Noggin also interacts with
growth differentiation factor 5
(
GDF5
), in which mutations have also been described in families with symphalangism. The latter is also the case for the BMP receptor BMPR1B to which
GDF5
binds. Finally, a mutation in another growth factor, fibroblast growth factor 9, was found in a family with multiple synostoses syndrome. In our patient, we could, however, not show a causative mutation in any of these genes, providing evidence for further genetic heterogeneity of this syndrome.
...
PMID:Negative mutation screening of the NOG, BMPR1B, GDF5, and FGF9 genes indicates further genetic heterogeneity of the facioaudiosymphalangism syndrome. 2296 93
Proximal symphalangism (SYM1) is an autosomal dominant disorder, mainly characterized by bony fusions of the proximal phalanges of the hands and feet.
GDF5
and
NOG
were identified to be responsible for SYM1. We have previously reported on a p.Leu373Arg mutation in the GDF5 proregion present in a Chinese family with SYM1. Here, we investigated the effects of the GDF-L373R mutation. The variant caused proteolysis efficiency of GDF5 increased in ATDC5 cells. The variant also caused upregulation of SMAD1/5/8 phosphorylation and increased expression of target genes
SMURF1
, along with
COL2A1
and
SOX9
which are factors associated with chondrosis. Furthermore, we developed a human-relevant SYM1 mouse model by making a
Gdf5
L367R
(the orthologous position for L373R in humans) knock-in mouse.
Gdf5
L367R/+
and
Gdf5
L367R/L367R
mice displayed stiffness and adhesions across the proximal phalanx joint which were in complete accord with SYM1. It was also confirmed the joint formation and development was abnormal in
Gdf5
L367R/+
and
Gdf5
L367R/L367R
mice, including the failure to develop the primary ossification center and be hypertrophic chondrocytes during embryonic development. This knock-in mouse model offers a tool for assessing the pathogenesis of SYM1 and the function of the GDF5 proregion.
...
PMID:Knock-in human GDF5 proregion L373R mutation as a mouse model for proximal symphalangism. 2937 61
