March 28th, 2013 update

Hello to everyone and thank you for your generous support.  These are very difficult times for medical research, especially for rare conditions like achondroplasia/hypochondroplasia.  The National Institutes of Health, which funds most medical research in the U.S., has had its budget cut even further with the sequester.  Less than 10% of grants are funded now and droves of people are leaving research.  Please tell your congressmen and senators to restore funding to the NIH!

On to research progress. The major thing occupying our time right now is the drug screen.

How do we do it?  

Let me explain how cartilage behaves first.  You find cartilage in your ears and nose (elastic cartilage because it bends), your joints (look at a chicken leg bone- the white, shiny part is the joint cartilage), and in the growing parts of the bone in children.  The way children grow in height is by making cartilage grow and turning it into bone (we call it the growth plate).  For example, in your thigh bone children have two growth plates- the one near your hip and the one near your knee.  See the figure below:

Thigh bone (femur) of a growing child.  The hip is at the top where the ball is and the knee at the bottom.  The growth plates are marked and colored.

 Growth plates look simple under the microscope but are very complicated organs.  Cartilage cells (the pink/blue dots in the figure below) are surrounded by the proteins that they make.  The protein consists of collagens that hold the cartilage together and make it tough and other proteins (proteoglycans) that have a lot of complex chains of sugar attached to them.  Proteoglycans attract water and so these proteins make cartilage cushion better (like when you put pressure on your joints while walking and running).  Farthest away from the bone are the resting cartilage cells that are less active and are the reserve (like players waiting on the bench).  The resting cells receive signals to divide and columns of dividing cells are formed in the proliferating zone.  They then receive additional signals and stop dividing and enlarge in size significantly in the hypertrophic zone closest to where new bone is formed.  These large cartilage cells produce calcium crystals around them.  Finally, these large cartilage cells die and protein containing calcium that they have made is replaced by regular bone.  This whole process is called endochondral ossification.

In achondroplasia and hypochondroplasia, the cartilage cells don't divide as fast, there is less protein between the cells, and the cells don't turn into hypertrophic zone cells very well.  All this causes the growth plate to be shortened and growth in children to be slowed.

Growth plates of a normal child (control on the left) and of a severe cousin of achondroplasia (thanatophoric dysplasia, on the right).  The newly formed bone would be at the bottom.

Fibroblast growth factor receptor 3 (FGFR3) acts as a brake for cartilage cells in the growth plate.  The genetic mutations that cause achondroplasia and hypochondroplasia increase the strength of the brake.  The way that the drug being tested by BioMarin works is to partially release the brake.  It can't release it all the way because it is only able to counteract part of what FGFR3 does.  That is why we are trying to find another medication using a drug screen.

For years, we have been using RCS cartilage cells to study how FGFR3 works.  RCS cells are cartilage cells that grow very well in a culture dish.  They have a lot of FGFR3.  In a culture dish, they normally look like round balls surrounded by a soft layer of cartilage proteins.

In the figure below, the control pictures are RCS cells grown in the culture dish.  On the bottom is what they look like with regular light.  On the top we have stained them with alcian blue, which is a stain for proteoglycans.  When we add fibroblast growth factor (FGF2), we turn on FGFR3.  With FGF2 you can see the cells have flattened out, attaching to the plastic at the bottom of the culture dish and no longer stain bright blue.  The cells have stopped growing, destroyed the proteoglycans around them, and changed their behavior.  They are more like primitive cells that haven't become cartilage cells yet.  Similar things are happening in the cartilage of children with achondroplasia.  If you treat the cells with a drug that blocks some of what FGFR3 does, you get improved growth.  You can see that CNP (related to BioMarin's drug) helps the cells act more normally.

You can use the RCS system to find new drugs.  Add a drug to RCS cells and treat them with FGF2.  If they grow better, you have a promising compound to test further.  The really nice part about using this way to find drugs is if the drug is toxic to cartilage cells, they cells won't grow better.  Eliminating toxic drugs is the usual headache for any drug screen.  

To test our system, we used this RCS system to screen 5000 compounds.  We did it by hand in a square plastic plate with 96 holes in it.  Cells are put in each hole with different drugs, FGF2 is added, and 3 days later we count cells.  If there are more cells, the drug may be doing something.  We found one good compound from this pilot screen, NF449.  It works very well to block FGFR3 and isn't toxic to the cells, but it would need modified to work well in humans.  A collaborator is trying to find where NF449 binds to FGFR3 so we can make those modifications.  Since developing any compound into a drug we can use in people is a long-shot, we want to do a bigger drug screen of 100,000+ compounds.  

Screening 100,000+ compounds by hand would be very expensive and time consuming, so we are working with the drug screening core facility at UCLA to use their robots.

In order to do the drug screen for less than a fortune, we have to do it in plastic plates with 384 holes.  These holes are very tiny as you can see below compared to my index finger.  The cells grow at the bottom of the holes.

Unfortunately, we can't just take the number of cells and the amount of FGF2 we used for the 96 well screen and scale down to a smaller size.  We have to test how many cells to use in each well (too many and they don't want to divide, too few and you don't have enough to measure) and how much FGF2 to use (too much and no drug could reverse the growth arrest, too little and you don't get any growth arrest).  We had to work out how to measure the number of cells quickly and by robot (you add a chemical that reacts with energy in cells and coverts it to light- the more living cells, the more light).  We had to make sure that the conditions would still detect NF449 as a potential drug.  We accomplished all of that and then went to use the robots to do the grunt work.  Darn it if the tubing used to suck up the FGF2 solution from a bottle didn't bind all the FGF2.  No FGF2 in the tiny wells, the cells grow normally.  This kind of problem isn't unheard of, but it is annoying.  We are working with the screening lab director to solve this problem.  Once it is solved and we verify everything works well, then we are off to the races and can screen all those drugs.  Stay tuned!

Bill Wilcox

January 18, 2013 Update

Information on the lab has been updated as has information on the status of the clinical trials.

Substantial progress has been made testing the drug screening platform.  We are conducting a small scale pilot screen to verify we are ready for the final step, a full scale drug screen.

Work continues on defining the signaling pathways used by FGFR3.

Dr. Krejci will be returning to the Czech Republic in April for a faculty position and to spend more time with his children.  We hope to continue to work with him on FGFR3 and wish him the best in his future research career.

A post-doctoral researcher will be recruited to continue the signaling pathway work to identify better therapeutic targets.  New bioinformatics tools will be employed to assemble the available data into networks.  This allows construction of a model for the pathways chondrocytes use even when there is missing data and lessens the need to dissect the pathways with extensive experimentation.  The post-doc will also be evaluating lead compounds identified in the drug screen.

October 3 Update

Pavel continues with his work to sort out the complicated signaling pathways used by FGFR3 in cartilage cells. 

Yuan and Jorge are at work optimizing the drug screening assay Pavel and I developed for a 384 well plate format.  We have done it before, by hand, in 96 well plates to screen 5,000 compounds.  We are going to screen 90,000+ this time using robots.  We have to use smaller volumes to make the screen affordable.  Converting from 96 wells to 384 wells sounds simple, but there is a lot of troubleshooting to do before we do the screen.

August 3, 2012 update

Yuan is working with the drug screening core at UCLA to screen over 90,000 chemical compounds for their effect on the RCS cell line, the model we use for drug screening to find treatments for achondroplasia.

Pavel and his collaborators have identified many new proteins involved in FGFR3 signaling using proteomics, a technique where the thousands of proteins in the cell are analyzed using mass spectrometry, a very sensitive way to analyze small samples.  He is in the process of validating some of the hits from the proteomic studies.  Understanding how FGFR3 signals is critical in identifying specific pathways to target.

We are working with 3 companies to acquire and test compounds they have made that are said to inhibit FGFRs.  We will test these compounds in the lab to see how specific they are for FGFR3 and if their structures could be modified to make them useful for achondroplasia.

Cedars-Sinai will be participating in the BioMarin trials of the CNP analogue.  Very shortly, we will start the measurement study in children 4.5 to 9 years of age.  Younger children will be enrolled at a later date.  At least 6 months of growth data is needed before a child would be considered for the drug study, once it starts.  The study will require several trips to Los Angeles.  If you have a child with achondroplasia and might be interested, contact Tara Funari at 310-423-4495 for more information.

June 18, 2012 update

We published a paper showing the interaction of the FGFR3 pathway with the Wnt pathway, now included in the publication list.  In cartilage cells, the Wnt pathway is critical in determining whether a cell progresses along the normal pathway of development in the growth area of the cartilage.  In less mature areas of cartilage, it can force a cartilage cell back to a more primitive type of cell.  FGFR3 over-activity, as in achondroplasia, causes over-activity of the Wnt pathway.  This helps explain some of the puzzling features of poor cartilage cell development in achondroplasia.

We are collaborating with another laboratory to determine where NF449 binds to FGFR3.  With this information, a better drug might be designed.

Over the summer, Dr. Xue will be doing the prerequisite experiments for the large scale drug screen (90,000+ compounds) to be run in the core facility at UCLA. Dr. Krejci will be continuing his studies of the FGFR3 signaling pathways to find better targets.

Wilcox lab

Background and Goals of the Wilcox lab:

The increase in height in animals is caused by a process called endochondral ossification.  Cartilage near the end of the bones increases in length and is replaced by bone.   This process is very complicated, not completely understood, and regulated by many genes and growth factor systems.  Hereditary variations in the different regulatory systems largely determine how tall you will be.  When growth ceases after puberty, the growth cartilage disappears. 

Achondroplasia, the related milder disorder hypochondroplasia, and the lethal disorder thanatophoric dysplasia are caused by mutations in the gene for Fibroblast growth factor receptor 3 (FGFR3).  All the mutations turn on the receptor excessively.  The more the receptor is turned on, the more severe the dwarfism.  Although there seems to be no excess cancer risk with the mild achondroplasia and hypochondroplasia mutations, the mutations in the lethal thanatophoric dysplasia have been associated with several cancers.  Why does excessive activity of FGFR3 cause more growth in some tissues but it causes growth cartilage to slow down how fast it increases in length?  The answer is still not clear.

FGFR3 is one of the major brakes on growth in cartilage.  How FGFR3 functions in cartilage cells is being sorted out in our lab, Dr. Horton’s lab, and a few others.  FGFR3 uses many pathways to cause its effects in cartilage cells and interacts with a number of the other important signaling pathways.  Some of the pathways we are just discovering now.

C-type natriuretic peptide (CNP) has been investigated by Dr. Kazuwa Nakao’s group in Kyoto, Japan.  They found that increasing CNP in the mouse could partially correct dwarfism in the achondroplasia mouse model.  We went on to elucidate some of the mechanisms for CNP action in cartilage cells and how it could partially block FGFR3’s actions.  Dr. Krejci and I took the CNP idea to biotechnology companies and interested BioMarin in the project.  They have gone on to develop a more stable form of CNP that has been shown to improve growth in a mouse model for achondroplasia and increase growth in normal monkeys. 

While CNP is a significant advance, it can only affect half of what FGFR3 is doing in cartilage cells and daily injections for the entire period a child is growing are inconvenient.  A longer lasting treatment or an oral drug would be ideal.  The challenge is to identify such a drug that will not cause significant side effects.  Dr. Krejci developed a drug screening method to identify drugs that interfere with FGFR3 and are not toxic to cells.  Using this method in a small scale screen of 5000 compounds, he identified NF449.  It and its relatives inhibit FGFR3 very well.  However, the structure of the NF449 and its relatives are such that it won’t make a good oral drug- it doesn’t get into cells easily by itself.  A larger drug screen (90,000+ compounds) should allow us to find better compounds. 

Clinical Studies:

People with achondroplasia tend to be obese and have high blood pressure, which is usually not properly treated.  These factors alone may be enough to explain the fact that achondroplasts tend to die 5-10 years younger.  However, FGFR3 is important in many areas of the body besides the growing cartilage.  We are currently conducting a study on adults with achondroplasia to find out if they are prediabetic and/or have abnormalities of their blood vessels. 

This drug related to CNP has been tested for safety in adults.  Trials in children with achondroplasia are expected to start later in 2013.  The drug will have to be injected every day, much like growth hormone (which is ineffective for increasing growth in dwarfs).  Dr. Wilcox will be one of the investigators in the trials.  Interested families with achondroplastic children should contact a local site for more information.  The precursor study is a measurement study.  Some patients in this study will be eligible to enter the drug trial.  The link for the measurement study is: 
http://www.clinicaltrials.gov/ct2/show/NCT01603095?term=NCT01603095&rank=1

For more information on these clinical studies, contact Tara Funari, M.S. at (310) 423-9915, email:  tara.funari@cshs.org

Meet the lab:

Pavel Krejci, Ph.D.

Dr. Krejci was born in what is now the Czech Republic.  He graduated with a bachelor’s degree in Biology from the Masaryk University in Brno.  He then went on to obtain his Ph.D. in Molecular Embryology at the Mendel University in Brno.  His graduate work concentrated on the role of fibroblast growth factors in leukemia.  He did post-doctoral fellowships in the Wilcox laboratory from 2001-2003 and in Toulouse, France from 2003-2004.  He then returned to Cedars-Sinai where he is a research scientist and member of the genetics faculty.  He is an Adjunct Associate Professor of Pediatrics through the UCLA School of Medicine.  Dr. Krejci has maintained his connections in the Czech Republic, where he is a research scientist and supervises graduate students in the Institute of Experimental Biology at Masaryk University in Brno.  He has obtained several grants in the Czech Republic to study FGF signaling and, now that he is a permanent resident of the U.S., applied for grant funding from the NIH.  The ongoing relationship between the U.S. and Czech Republic labs has been extremely helpful to our ongoing efforts to understand FGFR3 and find novel targets for treatment.

Dr. Krejci will continue to dissect the pathways FGFR3 uses to cause dwarfism so new targets can be identified.

Pavel has two children and enjoys hiking, backpacking, fishing, and is an accomplished naturalist.

Yuan Xue, M.D., Ph.D.

Dr. Xue was born in Wuhan, China.  In 2000, she obtained her M.D. degree from the Tongji Medical University in Wuhan.  She then came to the U.S. where she obtained her Ph.D. in 2006 from Kansas State University in Human Nutrition in Molecular Biochemistry.  After her Ph.D., she worked in two core laboratories at UCLA and Cedars-Sinai from 2007 to 2011.

In 2011, Dr. Xue joined the laboratory to study a treatment for achondroplasia being tested by a biotechnology company. 

Dr. Xue will be conducting a large scale drug screen using a modification of the screening system that Dr. Krejci developed and used to identify NF449.  The goal is to identify potential new drugs to treat achondroplasia.

Yuan enjoys hiking, traveling, art, and painting.

Jorge Martin, B.S.

Jorge joined the lab in 2011 as a senior technician after working for many years at U.C. Irvine.  Jorge is in charge of the tissue and cell collection from the International Skeletal Dysplasia Registry at Cedars-Sinai, an invaluable resource for studying dwarfisms. 

Jorge will be assisting Drs. Krejci and Xue with some of their work in the lab.

Jorge is an accomplished musician.

Publications from the Wilcox/Krejci Laboratory

Fibroblast growth factors:

Krejci P, Pejchalova K, Rosenbloom BE, Rosenfelt FP, Tran EL, Laurell H,

Wilcox WR. The antiapoptotic protein Api5 and its partner, high molecular weight

FGF2, are up-regulated in B cell chronic lymphoid leukemia. J Leukoc Biol. 2007

Dec;82(6):1363-4. Epub 2007 Sep 7. PubMed PMID: 17827341.

Krejci P, Krakow D, Mekikian PB, Wilcox WR. Fibroblast growth factors 1, 2,

17, and 19 are the predominant FGF ligands expressed in human fetal growth plate

cartilage. Pediatr Res. 2007 Mar;61(3):267-72. PubMed PMID: 17314681.

Krejci P, Mekikian PB, Wilcox WR. The fibroblast growth factors in multiple

myeloma. Leukemia. 2006 Jun;20(6):1165-8. PubMed PMID: 16598309.

Fibroblast growth factor signaling:

Krejci P, Aklian A, Kaucka M, Sevcikova E, Prochazkova J, Masek JK, Mikolka P,
Pospisilova T, Spoustova T, Weis M, Paznekas WA, Wolf JH, Gutkind JS, Wilcox WR,
Kozubik A, Jabs EW, Bryja V, Salazar L, Vesela I, Balek L.  Receptor Tyrosine Kinases Activate Canonical WNT/β-Catenin Signaling via MAP Kinase/LRP6 Pathway and Direct β-Catenin Phosphorylation.  PLoS One. 2012;7(4):e35826.  PMCID: PMC3338780 PMID: 22558232


Merrill AE, Sarukhanov A, Krejci P, Idoni B, Camacho N, Estrada KD, Lyons KM,

Deixler H, Robinson H, Chitayat D, Curry CJ, Lachman RS, Wilcox WR, Krakow D.

Bent Bone Dysplasia-FGFR2 type, a Distinct Skeletal Disorder, Has Deficient

Canonical FGF Signaling. Am J Hum Genet. 3012 Mar 9;90(3):550-557. Epub 2012 Mar

1. PubMed PMID: 22387015.

Červenka I, Wolf J, Mašek J, Krejci P, Wilcox WR, Kozubík A, Schulte G,

Gutkind JS, Bryja V. Mitogen-activated protein kinases promote WNT/beta-catenin

signaling via phosphorylation of LRP6. Mol Cell Biol. 2011 Jan;31(1):179-89. Epub

2010 Oct 25. PubMed PMID: 20974802; PubMed Central PMCID: PMC3019858.

Krejci P, Prochazkova J, Smutny J, Chlebova K, Lin P, Aklian A, Bryja V,

Kozubik A, Wilcox WR. FGFR3 signaling induces a reversible senescence phenotype

in chondrocytes similar to oncogene-induced premature senescence. Bone. 2010

Jul;47(1):102-10. Epub 2010 Mar 31. PubMed PMID: 20362703; PubMed Central PMCID:

PMC3087869.

Salazar L, Kashiwada T, Krejci P, Muchowski P, Donoghue D, Wilcox WR, Thompson

LM. A novel interaction between fibroblast growth factor receptor 3 and the p85

subunit of phosphoinositide 3-kinase: activation-dependent regulation of ERK by

p85 in multiple myeloma cells. Hum Mol Genet. 2009 Jun 1;18(11):1951-61. Epub

2009 Mar 13. PubMed PMID: 19286672; PubMed Central PMCID: PMC2902846.

Krejci P, Salazar L, Kashiwada TA, Chlebova K, Salasova A, Thompson LM, Bryja

V, Kozubik A, Wilcox WR. Analysis of STAT1 activation by six FGFR3 mutants

associated with skeletal dysplasia undermines dominant role of STAT1 in FGFR3

signaling in cartilage. PLoS One. 2008;3(12):e3961. Epub 2008 Dec 17. PubMed

PMID: 19088846; PubMed Central PMCID: PMC2597732.

Krejci P, Prochazkova J, Bryja V, Jelinkova P, Pejchalova K, Kozubik A,

Thompson LM, Wilcox WR. Fibroblast growth factor inhibits interferon gamma-STAT1

and interleukin 6-STAT3 signaling in chondrocytes. Cell Signal. 2009

Jan;21(1):151-60. Epub 2008 Oct 12. PubMed PMID: 18950705; PubMed Central PMCID:

PMC2655766.

Matsushita T, Wilcox WR, Chan YY, Kawanami A, Bükülmez H, Balmes G, Krejci P,

Mekikian PB, Otani K, Yamaura I, Warman ML, Givol D, Murakami S. FGFR3 promotes

synchondrosis closure and fusion of ossification centers through the MAPK

pathway. Hum Mol Genet. 2009 Jan 15;18(2):227-40. Epub 2008 Oct 15. PubMed PMID:

18923003; PubMed Central PMCID: PMC2638772.

Krejci P, Salazar L, Goodridge HS, Kashiwada TA, Schibler MJ, Jelinkova P,

Thompson LM, Wilcox WR. STAT1 and STAT3 do not participate in FGF-mediated growth

arrest in chondrocytes. J Cell Sci. 2008 Feb 1;121(Pt 3):272-81. Epub 2008 Jan

15. PubMed PMID: 18198189.

Krejci P, Masri B, Salazar L, Farrington-Rock C, Prats H, Thompson LM, Wilcox

WR. Bisindolylmaleimide I suppresses fibroblast growth factor-mediated activation

of Erk MAP kinase in chondrocytes by preventing Shp2 association with the Frs2

and Gab1 adaptor proteins. J Biol Chem. 2007 Feb 2;282(5):2929-36. Epub 2006 Dec

4. PubMed PMID: 17145761.

Drugs and drug screening technique:

Scuto A, Krejci P, Popplewell L, Wu J, Wang Y, Kujawski M, Kowolik C, Xin H,

Chen L, Wang Y, Kretzner L, Yu H, Wilcox WR, Yen Y, Forman S, Jove R. The novel

JAK inhibitor AZD1480 blocks STAT3 and FGFR3 signaling, resulting in suppression

of human myeloma cell growth and survival. Leukemia. 2011 Mar;25(3):538-50. Epub

2010 Dec 17. PubMed PMID: 21164517; PubMed Central PMCID: PMC3216671.

Krejci P, Murakami S, Prochazkova J, Trantirek L, Chlebova K, Ouyang Z, Aklian

A, Smutny J, Bryja V, Kozubik A, Wilcox WR. NF449 is a novel inhibitor of

fibroblast growth factor receptor 3 (FGFR3) signaling active in chondrocytes and

multiple myeloma cells. J Biol Chem. 2010 Jul 2;285(27):20644-53. Epub 2010 May

3. PubMed PMID: 20439987; PubMed Central PMCID: PMC2898326.

Krejci P, Pejchalova K, Wilcox WR. Simple, mammalian cell-based assay for

identification of inhibitors of the Erk MAP kinase pathway. Invest New Drugs.

2007 Aug;25(4):391-5. Epub 2007 Apr 26. PubMed PMID: 17458503.

Krejci P, Masri B, Fontaine V, Mekikian PB, Weis M, Prats H, Wilcox WR.

Interaction of fibroblast growth factor and C-natriuretic peptide signaling in

regulation of chondrocyte proliferation and extracellular matrix homeostasis. J

Cell Sci. 2005 Nov 1;118(Pt 21):5089-100. Epub 2005 Oct 18. PubMed PMID:

16234329.

Krejci P, Bryja V, Pachernik J, Hampl A, Pogue R, Mekikian P, Wilcox WR. FGF2

inhibits proliferation and alters the cartilage-like phenotype of RCS cells. Exp

Cell Res. 2004 Jul 1;297(1):152-64. PubMed PMID: 15194433.

Clinical and molecular:

Danielpour M, Wilcox WR, Alanay Y, Pressman BD, Rimoin DL. Dynamic

cervicomedullary cord compression and alterations in cerebrospinal fluid dynamics

in children with achondroplasia. Report of four cases. J Neurosurg. 2007

Dec;107(6 Suppl):504-7. PubMed PMID: 18154022.

Schweitzer DN, Graham JM Jr, Lachman RS, Jabs EW, Okajima K, Przylepa KA,

Shanske A, Chen K, Neidich JA, Wilcox WR. Subtle radiographic findings of

achondroplasia in patients with Crouzon syndrome with acanthosis nigricans due to

an Ala391Glu substitution in FGFR3. Am J Med Genet. 2001 Jan 1;98(1):75-91.

Review. PubMed PMID: 11426459.

Kitoh H, Brodie SG, Kupke KG, Lachman RS, Wilcox WR. Lys650Met substitution

in the tyrosine kinase domain of the fibroblast growth factor receptor gene

causes thanatophoric dysplasia Type I. Mutations in brief no. 199. Online. Hum

Mutat. 1998;12(5):362-3. PubMed PMID: 10671061.

Bellus GA, Bamshad MJ, Przylepa KA, Dorst J, Lee RR, Hurko O, Jabs EW, Curry

CJ, Wilcox WR, Lachman RS, Rimoin DL, Francomano CA. Severe achondroplasia with

developmental delay and acanthosis nigricans (SADDAN): phenotypic analysis of a

new skeletal dysplasia caused by a Lys650Met mutation in fibroblast growth factor

receptor 3. Am J Med Genet. 1999 Jul 2;85(1):53-65. PubMed PMID: 10377013.

Brodie SG, Kitoh H, Lachman RS, Nolasco LM, Mekikian PB, Wilcox WR.

Platyspondylic lethal skeletal dysplasia, San Diego type, is caused by FGFR3

mutations. Am J Med Genet. 1999 Jun 11;84(5):476-80. PubMed PMID: 10360402.

Tavormina PL, Bellus GA, Webster MK, Bamshad MJ, Fraley AE, McIntosh I, Szabo

J, Jiang W, Jabs EW, Wilcox WR, Wasmuth JJ, Donoghue DJ, Thompson LM, Francomano

CA. A novel skeletal dysplasia with developmental delay and acanthosis nigricans

is caused by a Lys650Met mutation in the fibroblast growth factor receptor 3

gene. Am J Hum Genet. 1999 Mar;64(3):722-31. PubMed PMID: 10053006; PubMed

Central PMCID: PMC1377789.

Brodie SG, Kitoh H, Lipson M, Sifry-Platt M, Wilcox WR. Thanatophoric

dysplasia type I with syndactyly. Am J Med Genet. 1998 Nov 16;80(3):260-2. PubMed

PMID: 9843049.

Kitoh H, Lachman RS, Brodie SG, Mekikian PB, Rimoin DL, Wilcox WR. Extra

pelvic ossification centers in thanatophoric dysplasia and platyspondylic lethal

skeletal dysplasia-San Diego type. Pediatr Radiol. 1998 Oct;28(10):759-63. PubMed

PMID: 9799297.

Wilcox WR, Tavormina PL, Krakow D, Kitoh H, Lachman RS, Wasmuth JJ, Thompson

LM, Rimoin DL. Molecular, radiologic, and histopathologic correlations in

thanatophoric dysplasia. Am J Med Genet. 1998 Jul 7;78(3):274-81. PubMed PMID:

9677066.

Tavormina PL, Shiang R, Thompson LM, Zhu YZ, Wilkin DJ, Lachman RS, Wilcox

WR, Rimoin DL, Cohn DH, Wasmuth JJ. Thanatophoric dysplasia (types I and II)

caused by distinct mutations in fibroblast growth factor receptor 3. Nat Genet.

1995 Mar;9(3):321-8. PubMed PMID: 7773297.

Reviews:

Foldynova-Trantirkova S, Wilcox WR, Krejci P. Sixteen years and counting: the

current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in

skeletal dysplasias. Hum Mutat. 2012 Jan;33(1):29-41. doi: 10.1002/humu.21636.

Epub 2011 Nov 16. PubMed PMID: 22045636; PubMed Central PMCID: PMC3240715.

Krejci P, Prochazkova J, Bryja V, Kozubik A, Wilcox WR. Molecular pathology of

the fibroblast growth factor family. Hum Mutat. 2009 Sep;30(9):1245-55. Review.

PubMed PMID: 19621416; PubMed Central PMCID: PMC2793272.

Chlebova K, Bryja V, Dvorak P, Kozubik A, Wilcox WR, Krejci P. High molecular

weight FGF2: the biology of a nuclear growth factor. Cell Mol Life Sci. 2009

Jan;66(2):225-35. Review. PubMed PMID: 18850066; PubMed Central PMCID:

PMC3229932.

Pejchalova K, Krejci P, Wilcox WR. C-natriuretic peptide: an important

regulator of cartilage. Mol Genet Metab. 2007 Nov;92(3):210-5. Epub 2007 Aug 6.

Review. PubMed PMID: 17681481.

Passos-Bueno MR, Wilcox WR, Jabs EW, Sertié AL, Alonso LG, Kitoh H. Clinical

spectrum of fibroblast growth factor receptor mutations. Hum Mutat.

1999;14(2):115-25. Erratum in: Hum Mutat 2001 May;17(5):431. PubMed PMID:

10425034.