这是与CWRU合作的文章。
1: J Clin Invest. 2005 Mar;115(3):622-31.
The secreted glycoprotein lubricin protects cartilage surfaces and inhibits
synovial cell overgrowth.
Rhee DK, Marcelino J, Baker M, Gong Y, Smits P, Lefebvre V, Jay GD, Stewart M,
Wang H, Warman ML, Carpten JD.
Department of Genetics, Center for Human Genetics, Case Western Reserve
University School of Medicine and University Hospitals of Cleveland, Cleveland,
Ohio 44106, USA.
The long-term integrity of an articulating joint is dependent upon the
nourishment of its cartilage component and the protection of the cartilage
surface from friction-induced wear. Loss-of-function mutations in lubricin (a
secreted glycoprotein encoded by the gene PRG4) cause the human autosomal
recessive disorder camptodactyly-arthropathy-coxa vara-pericarditis syndrome
(CACP). A major feature of CACP is precocious joint failure. In order to
delineate the mechanism by which lubricin protects joints, we studied the
expression of Prg4 mRNA during mouse joint development, and we created
lubricin-mutant mice. Prg4 began to be expressed in surface chondrocytes and
synoviocytes after joint cavitation had occurred and remained strongly expressed
by these cells postnatally. Mice lacking lubricin were viable and fertile. In
the newborn period, their joints appeared normal. As the mice aged, we observed
abnormal protein deposits on the cartilage surface and disappearance of
underlying superficial zone chondrocytes. In addition to cartilage surface
changes and subsequent cartilage deterioration, intimal cells in the synovium
surrounding the joint space became hyperplastic, which further contributed to
joint failure. Purified or recombinant lubricin inhibited the growth of these
synoviocytes in vitro. Tendon and tendon sheath involvement was present in the
ankle joints, where morphologic changes and abnormal calcification of these
structures were observed. We conclude that lubricin has multiple functions in
articulating joints and tendons that include the protection of surfaces and the
control of synovial cell growth.
PMID: 15719068 [PubMed - indexed for MEDLINE]
2: Mol Cell Biol. 2005 Jan;25(1):414-21.
WISP3, the gene responsible for the human skeletal disease progressive
pseudorheumatoid dysplasia, is not essential for skeletal function in mice.
Kutz WE, Gong Y, Warman ML.
Department of Genetics, Case Western Reserve University, 2109 Adelbert Road, BRB
719, Cleveland, OH 44106-4955, USA.
In humans, loss-of-function mutations in WISP3 cause the autosomal recessive
skeletal disease progressive pseudorheumatoid dysplasia (PPD) (Online Mendelian
Inheritance in Man database number 208230). WISP3 encodes Wnt1-inducible
signaling protein 3, a cysteine-rich, multidomain, secreted protein, whose
paralogous CCN (connective tissue growth factor/cysteine-rich protein
61/nephroblastoma overexpressed) family members have been implicated in diverse
biologic processes including skeletal, vascular, and neural development. To
understand the role of WISP3 in the skeleton, we targeted the Wisp3 gene in mice
by creating a mutant allele comparable to that which causes human disease. We
also created transgenic mice that overexpress human WISP3 in cartilage.
Surprisingly, homozygous Wisp3 mutant mice appear normal and do not recapitulate
any of the morphological, radiographic, or histological abnormalities seen in
patients with PPD. Mice that overexpress WISP3 are also normal. We conclude,
that in contrast to humans, Wisp3 is not an essential participant during
skeletal growth or homeostasis in mice.
PMID: 15601861 [PubMed - indexed for MEDLINE]
3: Am J Hum Genet. 2003 Mar;72(3):763-71. Epub 2003 Feb 10.
Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene
in different conditions with an increased bone density.
Van Wesenbeeck L, Cleiren E, Gram J, Beals RK, Benichou O, Scopelliti D, Key L,
Renton T, Bartels C, Gong Y, Warman ML, De Vernejoul MC, Bollerslev J, Van Hul
W.
Department of Medical Genetics, University of Antwerp, Antwerp, Belgium.
Bone is a dynamic tissue that is subject to the balanced processes of bone
formation and bone resorption. Imbalance can give rise to skeletal pathologies
with increased bone density. In recent years, several genes underlying such
sclerosing bone disorders have been identified. The LDL receptor-related protein
5 (LRP5) gene has been shown to be involved in both osteoporosis-pseudoglioma
syndrome and the high-bone-mass phenotype and turned out to be an important
regulator of peak bone mass in vertebrates. We performed mutation analysis of
the LRP5 gene in 10 families or isolated patients with different conditions with
an increased bone density, including endosteal hyperostosis, Van Buchem disease,
autosomal dominant osteosclerosis, and osteopetrosis type I. Direct sequencing
of the LRP5 gene revealed 19 sequence variants. Thirteen of these were confirmed
as polymorphisms, but six novel missense mutations (D111Y, G171R, A214T, A214V,
A242T, and T253I) are most likely disease causing. Like the previously reported
mutation (G171V) that causes the high-bone-mass phenotype, all mutations are
located in the aminoterminal part of the gene, before the first epidermal growth
factor-like domain. These results indicate that, despite the different diagnoses
that can be made, conditions with an increased bone density affecting mainly the
cortices of the long bones and the skull are often caused by mutations in the
LRP5 gene. Functional analysis of the effects of the various mutations will be
of interest, to evaluate whether all the mutations give rise to the same
pathogenic mechanism.
PMID: 12579474 [PubMed - indexed for MEDLINE]
4: Cell. 2001 Nov 16;107(4):513-23.
LDL receptor-related protein 5 (LRP5) affects bone accrual and eye development.
Gong Y, Slee RB, Fukai N, Rawadi G, Roman-Roman S, Reginato AM, Wang H, Cundy T,
Glorieux FH, Lev D, Zacharin M, Oexle K, Marcelino J, Suwairi W, Heeger S,
Sabatakos G, Apte S, Adkins WN, Allgrove J, Arslan-Kirchner M, Batch JA,
Beighton P, Black GC, Boles RG, Boon LM, Borrone C, Brunner HG, Carle GF,
Dallapiccola B, De Paepe A, Floege B, Halfhide ML, Hall B, Hennekam RC, Hirose
T, Jans A, Juppner H, Kim CA, Keppler-Noreuil K, Kohlschuetter A, LaCombe D,
Lambert M, Lemyre E, Letteboer T, Peltonen L, Ramesar RS, Romanengo M, Somer H,
Steichen-Gersdorf E, Steinmann B, Sullivan B, Superti-Furga A, Swoboda W, van
den Boogaard MJ, Van Hul W, Vikkula M, Votruba M, Zabel B, Garcia T, Baron R,
Olsen BR, Warman ML; Osteoporosis-Pseudoglioma Syndrome Collaborative Group.
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.
PMID: 11719191 [PubMed - indexed for MEDLINE]
5: J Biol Chem. 1999 Aug 6;274(32):22469-75.
Complete sequence of the 23-kilobase human COL9A3 gene. Detection of Gly-X-Y
triplet deletions that represent neutral variants.
Paassilta P, Pihlajamaa T, Annunen S, Brewton RG, Wood BM, Johnson CC, Liu J,
Gong Y, Warman ML, Prockop DJ, Mayne R, Ala-Kokko L.
Collagen Research Unit, Biocenter and Department of Medical Biochemistry,
University of Oulu, Kajaanintie 52A, FIN-90220 Oulu, Finland.
We report the complete sequence of the human COL9A3 gene that encodes the alpha3
chain of heterotrimeric type IX collagen, a member of the fibril-associated
collagens with interrupted triple helices family of collagenous proteins.
Nucleotide sequencing defined over 23,000 base pairs (bp) of the gene and about
3000 bp of the 5'-flanking sequences. The gene contains 32 exons. The domain and
exon organization of the gene is almost identical to a related gene, the human
COL9A2 gene. However, exon 2 of the COL9A3 gene codes for one -Gly-X-Y- triplet
less than exon 2 of the COL9A2 gene. The difference is compensated by an
insertion of 9 bp coding for an additional triplet in exon 4 of the COL9A3 gene.
As a result, the number of -Gly-X-Y- repeats in the third collagenous domain
remains the same in both genes and ensures the formation of an in-register
triple helix. In the course of screening this gene for mutations, heterozygosity
for separate 9-bp deletions within the COL1 domain were identified in two
kindreds. In both instances, the deletions did not co-segregate with any disease
phenotype, suggesting that they were neutral variants. In contrast, similar
deletions in triple helical domain of type I collagen are lethal. To study
whether alpha3(IX) chains with the deletion will participate in the formation of
correctly folded heterotrimeric type IX collagen, we expressed mutant alpha3
chains together with normal alpha1 and alpha2 chains in insect cells. We show
here that despite the deletion, mutant alpha3 chains were secreted as
heterotrimeric, triple helical molecules consisting of three alpha chains in a
1:1:1 ratio. The results suggest that the next noncollagenous domain (NC2) is
capable of correcting the alignment of the alpha chains, and this ensures the
formation of an in-register triple helix.
PMID: 10428822 [PubMed - indexed for MEDLINE]
6: Nat Genet. 1999 Mar;21(3):302-4.
Heterozygous mutations in the gene encoding noggin affect human joint
morphogenesis.
Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-Hirji R, Hudgins L,
Cremers CW, Cremers FP, Brunner HG, Reinker K, Rimoin DL, Cohn DH, Goodman FR,
Reardon W, Patton M, Francomano CA, Warman ML.
Department of Genetics and Center for Human Genetics, Case Western Reserve
University School of Medicine and University Hospitals of Cleveland, Ohio, USA.
The secreted polypeptide noggin (encoded by the Nog gene) binds and inactivates
members of the transforming growth factor beta superfamily of signalling
proteins (TGFbeta-FMs), such as BMP4 (ref. 1). By diffusing through
extracellular matrices more efficiently than TGFbeta-FMs, noggin may have a
principal role in creating morphogenic gradients. During mouse embryogenesis,
Nog is expressed at multiple sites, including developing bones. Nog-/- mice die
at birth from multiple defects that include bony fusion of the appendicular
skeleton. We have identified five dominant human NOG mutations in unrelated
families segregating proximal symphalangism (SYM1; OMIM 185800) and a de novo
mutation in a patient with unaffected parents. We also found a dominant NOG
mutation in a family segregating multiple synostoses syndrome (SYNS1; OMIM
186500); both SYM1 and SYNS1 have multiple joint fusion as their principal
feature. All seven NOG mutations alter evolutionarily conserved amino acid
residues. The findings reported here confirm that NOG is essential for joint
formation and suggest that NOG requirements during skeletogenesis differ between
species and between specific skeletal elements within species.
PMID: 10080184 [PubMed - indexed for MEDLINE]
7: Am J Hum Genet. 1999 Feb;64(2):570-7.
Brachydactyly type B: clinical description, genetic mapping to chromosome 9q,
and evidence for a shared ancestral mutation.
Gong Y, Chitayat D, Kerr B, Chen T, Babul-Hirji R, Pal A, Reiss M, Warman ML.
Department of Genetics and Center for Human Genetics, Case WesternReserve
University School of Medicine and University Hospitals of Cleveland, Cleveland,
OH, USA.
Autosomal dominant brachydactyly type B (BDB) is characterized by nail aplasia
with rudimentary or absent distal and middle phalanges. We describe two
unrelated families with BDB. One family is English; the other family is Canadian
but of English ancestry. We assigned the BDB locus in the Canadian family to an
18-cM interval on 9q, using linkage analysis (LOD score 3.5 at recombination
fraction [theta] 0, for marker D9S938). Markers across this interval also
cosegregated with the BDB phenotype in the English family (LOD score 2.1 at
straight theta=0, for marker D9S277). Within this defined interval is a smaller
(7.5-cM) region that contains 10 contiguous markers whose disease-associated
haplotype is shared by the two families. This latter result suggests a common
founder among families of English descent that are affected with BDB.
PMID: 9973295 [PubMed - indexed for MEDLINE]
8: Cytogenet Cell Genet. 1998;81(3-4):205-7.
Physical and linkage mapping of the gene for the alpha3 chain of type IX
collagen, COL9A3, to human chromosome 20q13.3.
Tiller GE, Warman ML, Gong Y, Knoll JH, Mayne R, Brewton RG.
Departments of Pediatrics and Medicine, Vanderbilt University School of
Medicine, Nashville, TN, USA.
tiller@mcmail.vanderbilt.eduType IX collagen is a minor cartilage component which associates with mixed
fibrils of types II/XI collagen. We have determined the precise physical and
genetic locations for the gene encoding the alpha3 chain of type IX collagen,
COL9A3. Utilizing fluorescence in situ hybridization, radiation hybrid mapping,
and multipoint linkage analysis, we have mapped COL9A3 to human chromosome
20q13.3, 13 cM telomeric to D20S173.
PMID: 9730604 [PubMed - indexed for MEDLINE]
