Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Pivot Concepts:
Gene/Protein
Disease
Symptom
Drug
Enzyme
Compound
Target Concepts:
Gene/Protein
Disease
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Query: UNIPROT:P43026 (
lipopolysaccharide
)
62,215
document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)
Growth/differentiation factor 5
(
GDF5
) is a secreted growth factor that plays a key regulatory role in embryonic skeletal and joint development. Mutations in the
GDF5
gene can cause different types of skeletal dysplasia, including brachydactyly type C (BDC) and proximal symphalangism (
SYM1
). We report two novel mutations in the
GDF5
gene in Chinese families with distinct limb malformations. In one family affected with BDC, we identified a novel nonsense mutation, c.1461T > G (p.Y487X), which is predicted to truncate the
GDF5
precursor protein by deleting 15 amino acids at its C-terminus. In one family with
SYM1
, we found a novel missense mutation, c.1118T > G (p.L373R), which changes a highly conserved amino acid in the prodomain of
GDF5
. We transfected COS-7 cells with retroviral constructs to express human wild-type or mutant
GDF5
cDNAs. The mature GDF5 protein was detected, as in the wild-type, in supernatant derived from the p.L373R mutant
GDF5
transfected cells, but not in the supernatant from the p.Y487X mutant transfected cells, indicating that the two mutations led to different fates of the mutant
GDF5
proteins, thereby producing distinct limb phenotypes.
...
PMID:Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. 1828 15
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
