a novel mutation in gdf5 causes autosomal dominant symphalangism in two chinese families

� 2006 Wiley-Liss, Inc. American Journal of Medical Genetics Part A 140A:1846–1853 (2006)

A Novel Mutation in GDF5 Causes AutosomalDominant Symphalangism in Two Chinese Families

Xu Wang,1 Fuying Xiao,2 Qinbo Yang,1 Bo Liang,3 Zhaohui Tang,1 Linbin Jiang,2

Qihui Zhu,1 Wei Chang,1 Jiuxi Jiang,2 Chuanming Jiang,2 Xiang Ren,1

Jing-Yu Liu,1 Qing K. Wang,1,4** and Mugen Liu1*1Human Genome Research Center and College of Life Science and Technology,

Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China2Department of Biotechnology, Guilin Medical College, Guangxi, P. R. China

3Institute of Radiology, the Union Hospital, Tongji Medical College,Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China

4Department of Molecular Cardiology, Lerner Research Institute, and Center for Cardiovascular Genetics,The Cleveland Clinic Foundation, Cleveland, Ohio

Received 18 January 2006; Accepted 16 May 2006

Proximal symphalangism (SYM1) is an autosomal dominantdisorder characterized by ankylosis of the proximal inter-phalangeal joints and fusion of carpal and tarsal bones. Weidentified and characterized two five-generation Chinesefamilies with SYM1. The two families share some similarities(e.g., osseous fusion of interphalangeal joints of the 2–4 fingers) with SYM1 families with mutations in the NOGgene or the family with mutation R438L recently reported inthe GDF5 gene (encoding a bone morphogenetic proteinfamily member). However, they show some unique featuresincluding the absence of cuboid bone, the lack of shortnessof the first and fifth metacarpal bones, and manifestationof flat feet. Genome-wide linkage analysis of the twofamilies mapped the disease gene to marker D20S112 witha combined LOD score of 4.32. Mutational analysis revealed

a novel E491K mutation in the GDF5 gene in both families.The mutation occurs at a highly conserved residue in theTGF-b domain of GDF5 and represents the second GDF5mutation identified for SYM1 to date. The E491K mutationco-segregated with the affected individuals in the twofamilies, and did not exist in unaffected family members or200 normal controls. These results indicate that defectsin GDF5 can cause SYM1 in the Chinese population, andexpand the spectrum of clinical phenotypes associated withmutant GDF5. � 2006 Wiley-Liss, Inc.

Key words: GDF5; CDMP1; mutation; symphalangism;TGF-b domain

How to cite this article:WangX, Xiao F, YangQ, Liang B, Tang Z, Jiang L, ZhuQ, ChangW, Jiang J, Jiang C, RenX,Liu J-Y, Wang QK, Liu M. 2006. A novel mutation in GDF5 causes autosomal dominant symphalangism in two

Chinese families. Am J Med Genet Part A 140A:1846–1853.

INTRODUCTION

Proximal symphalangism (SYM1) (OMIM 185800)is an autosomal dominant disorder characterized byankylosis of the proximal interphalangeal joints,fusion of carpal and tarsal bones, and in some casesconductive deafness [Cushing, 1916; Strasburgeret al., 1965]. To date, two genes for SYM1 have beenidentified. The first SYM1 disease gene was identifiedas the NOG gene (encoding noggin) in six patients[Gong et al., 1999]. NOG encodes a bone morpho-genetic protein (BMP) antagonist and is essential forjoint formation in humans [Zimmerman et al., 1996;Gong et al., 1999]. Heterozygous missense mutationsin NOG result in not only SYM1, but also multiplesynostoses syndrome (SYNS1) [Gong et al., 1999;

This article contains supplementary material, which may be viewedat the American Journal of Medical Genetics website at http://www.interscience.wiley.com/jpages/1552-4825/suppmat/index.html.

Grant sponsor: Tenth ‘‘Five-Year’’ National Science and TechnologyKey Program of China; Grant number: 2004BA720A; Grant sponsor:National Natural Science Foundation of China; Grant number: 30470982;Grant sponsor: Chinese Ministry of Science and TechnologyNational High Technology ‘‘863’’ Programs of China; Grant number:2002BA711A07.

*Correspondence to: Dr. Mugen Liu, Huazhong University of Scienceand Technology Human Genome Research Center, Wuhan 430074, P. R.China. E-mail: [email protected]

**Correspondence to: Dr. Qing K. Wang, Huazhong University ofScience and Technology Human Genome Research Center, Wuhan430074, P. R. China; Center for Cardiovascular Genetics, The ClevelandClinic Foundation, Cleveland, OH 44195. E-mail: [email protected]

DOI 10.1002/ajmg.a.31372

Takahashi et al., 2001; Brown et al., 2002] and tarsal/carpal coalition syndrome (TCC) [Dixon et al., 2001].

Recently, one mutation in the growth/differentia-tion factor 5 gene (GDF5), R438L, was identified inone family with SYM1 [Seemann et al., 2005]. TheGDF5 gene was also referred to as the cartilage-derived morphogenetic protein-1 gene (CDMP1). Itencodes a member of the transforming growth factorbeta (TGF-b) family. Mutations in theGDF5 gene canalso result in other types of defects, including brachy-dactyly type C (BDC, OMIM 113100) [Polinkovskyet al., 1997; Savarirayan et al., 2003; Schwabe et al.,2004], brachydactyly type A2 (BDA2, OMIM 112600)[Seemann et al., 2005], Hunter–Thompson typechondrodysplasia (CHTT, OMIM 201250) [Thomaset al., 1996], chondrodysplasia Grebe type (CGT,OMIM 200700) [Thomas et al., 1997; Faiyaz-Ul-Haque et al., 2002a], DuPan syndrome (OMIM228900) [Faiyaz-Ul-Haque et al., 2002b], congenitalvertical talus (CVT, OMIM 192950) [Dobbs et al.,2005], and multiple-synostosis syndrome (SYNS1,OMIM 186500) [Dawson et al., 2006].

Mutations in the GDF5 gene result in the clinicalfeatures ranging from the mild deformation of singledigits to extreme shortening of all upper and lowerlimb skeletal elements [Schreuder et al., 2005]. Themechanism for the wide spectrum of phenotypicvariations is unknown. Recent functional studiesbegin to shed some lights on this issue. Two GDF5mutations, L441P for brachydactyly type A2 andR438L for SYM1, showed different receptor-bindingaffinities [Seemann et al., 2005]. Mutant GDF5 withmutation L441P lost the binding affinity to itsreceptors, BMP receptor type 1a (BMPR1A) and 1b(BMPR1B). In contrast, the R438L mutation increasedbinding of GDF5 to BMPR1A.

In this study,we report the SYM1clinical features intwofive-generationChinese families. Further geneticanalysis identified the linkage of the disease in thetwo families to the GDF5 gene and a novel mutationE491K in this gene. These results will enhance our

understanding of GDF5 function and provideinsights into the clinical spectrum of SYM1 causedby GDF5 mutations.

METHODS

Study Subjects and Isolation ofHuman Genomic DNA

The patients were identified and enrolled in thisstudy at the Hospital of Guilin Medical College.Informed consentwas obtained from theparticipantsin accordance with the study protocols approved bythe Ethics Committee of Huazhong University ofScience and Technology.

The members of the two families or their closerelatives were contacted and underwent clinicalassessment by means of a detailed questionnaire.Detailed records on medical history and physicalexaminations were obtained. The clinical findings inthe subjects of patients were summarized in Tables Iand II.

Peripheral blood samples from subjects wereobtained and genomic DNA was isolated from thewhole blood with the DNA Isolation Kit forMammalian Blood (Roche Diagnostic Co., Indiana-polis, IN).

Linkage Analysis

Two polymorphic markers D17S1868 andD17S787wereused for linkage analysis to determinewhether the known SYM1gene,NOG, is linked to thetwo Chinese families. After excluding the possibilityof the NOG gene as the disease-causing gene in thetwo families, a genome-wide scan was carried outwith 382 polymorphic microsatellite markers onchromosomes 1–22 (the ABI Prism Linkage 2.5 setMD10). Genotypes were analyzed using GeneMap-per 2.5 Software (Applied Biosystems, Foster City,CA). Pairwise logarithm of the odds (LOD) scores

TABLE I. Clinical Characters of Affected Individuals in Family 1

Pedigreenumber

Right fingers Left fingers

Wrist Right foot Left foot1 2 3 4 5 1 2 3 4 5

II:6 fp fp fp fp fp fp ch tf tfIII:2 fp fp fp fp fp dp tp tf ac, tmIII:4 fp fp fp fp fp fp ch tf tmIV:2 fp fp fp fp fp tt ac, tm tfIV:4 fp fp fp fp fp dp tt tm tfIV:6 fp fp fp fp fp fp fp tt tm tfIV:8 fp fp dp fp fp dp tt ac, tm ac, tmIV:10 fp fp fp fp fp fp ch tf tmV:1 df df df df dfV:2 df df df df

fp, a fused proximal joint; ds, a little short phalange; dp, a fused distal joint; df, a tendency fusion of proximal joint; tt, thefusion between trapezium bone and trapezoidbone; ch, the fusion between capitate bone andhamate bone; tp, the fusionbetween triquetral bone and pisiform bone; tf, fusion between tarsals; tm, fusion between tarsal and metatarsus; ac,indicates absence of cuboid bone.

A NOVEL MUTATION IN GDF5 GENE 1847

American Journal of Medical Genetics Part A: DOI 10.1002/ajmg.a

were calculated with the Linkage Package 5.2assuming the autosomal dominant inheritance pat-tern, a gene frequency of 0.001, a full penetrancerate, and an allele frequency of 1/n, where n equalsthe number of alleles observed [Wang et al., 2005].

Mutation Analysis

The linkage analysis andhaplotype resultsmappedthe disease gene in Family 1 to 20p12.1-q12, thelocation of GDF5. Mutation screening was per-formed using direct DNA sequence analysis. Theentire coding region of the GDF5 gene (two exons)and the exon–intron boundary sequences wereamplified by polymerase chain reaction (PCR).The primers designed for the PCR amplification arelisted in the online Table III (see the online Table IIIat http://www. interscience.wiley.com/jpages/1552-4825/suppmat/index.html). PCR was performed asdescribed previously [Wang et al., 2005]. The PCRproducts were separated on a 2% agarose gel andextracted using the QIAquick Gel Extraction Kit(Qiagen Inc., Valencia, CA), and sequenced withboth forward and reverse primers (the online TableIII). DNA sequence analysis was carried out usingthe BigDye Terminator Cycle Sequencing v3.1 kitand an ABI PRISM 3100 Genetic Analyzer (AppliedBiosystems).

SSCP (Single-Strand ConformationPolymorphism) Analysis

SSCP analysis was performed to confirm whetherthe mutation co-segregates with the disease in thetwo families. The 286-bp fragment of exon 2 ofGDF5containing the region carrying the heterozygousmutation was amplified by PCR. The primers forthe amplification were the same as the fifth pairlisted in the online Table III (see the online Table IIIat http://www. interscience.wiley.com/jpages/1552-4825/suppmat/index.html). SSCP analysis in Family1 and Family 2 was performed using the standardmethod described previously [Chen et al., 1998].DNA sample from 200 Chinese healthy controls

were screened to test the presence/absence of themutation.

RESULTS

Clinical Characterization of Two ChineseFamilies With SYM1

Two large Chinese families with 55 living familymembers were identified and characterized, amongwhich 17 have the clinical diagnosis of SYM1. Allpatients in the family showed the similar clinicalfeatures. The adult stature of the affected memberswas indistinguishable from the unaffected membersof the two families. The affected members havenormal intelligence. Patients were unable to flexfingers at the proximal interphalangeal joint. Radio-graphy of the hands (Fig. 1A) showed bilateralproximal interphalangeal joint osseous fusion offingers 2–4, distal interphalangeal joint fusion of thefifth digits, and sometimes the proximal interpha-langeal joint osseous fusion of the fifth finger(Fig. 1B). More than half of the affected patientsdisplayedflat feet (Fig. 1E) and reducedflexionof theankle bony prominences on the exterior of the feet.Foot radiography showed that the second and thethird cuneiform bones were fused to the second andthe third metatarsus bones; the second cuneiformbone was fused to the third cuneiform bonesrespectively, and scaphoid was fused to talus; theabsence of cuboid bone and the fusion betweenscaphoid and talus (Fig. 1C,D). Audiology showedno hearing abnormality in affected individuals of thetwo families. The spinal columns of the affectedindividuals were normal and the patients did nothave any other clinical problems such as facialabnormalities, humeroradial fusion, abnormalities ofthe elbow, painful and difficult ambulation of ankleand foot.

The bony fusions in the family are progressive, andyounger patients tend to present with less severephenotype. The radiography of the hands from ayoung patient in Family 1 is shown in Figure 2(individual V:2, Fig. 3A). The radiography showed

TABLE II. Clinical Characters of Affected Individuals in Family 2

Pedigreenumber

Right fingers Left fingers

Wrist Right foot Left foot1 2 3 4 5 1 2 3 4 5

III:4 fp fp dp fp fp fp dp ch ac, tm ac, tmIII:6 fp fp fp fp fp dp tt tf tfIV:1 fp fp fp fp fp dp tp tm tmIV:5 fp fp fp fp fp fp dp tt ac, tm ac,tmIV:6 fp fp fp fp fp fp fp fp tt tf tfIV:8 ds fp fp tp, ch tf tfV:1 fp fp dp fp fp dp tt ac, tf ac, tm

fp, a fused proximal joint; ds, a little short phalange; dp, a fused distal joint; df, a tendency fusion of proximal joint; tt, thefusion between trapezium bone and trapezoid bone; ch, the fusion between capitate bone and hamate bone; tp, the fusionbetween triquetral bone and pisiform bone; tf, fusion between tarsals; tm, fusion between tarsal and metatarsus; ac,indicates absence of cuboid bone.

1848 WANG ET AL.


the obvious tendency of interphalangeal joint oss-eous fusions of the 4th–5th fingers in both hands.The gaps between the distal end of the proximalphalanx and the proximal end of the middle phalanxturned out to be much narrower than other normalgaps. The radiography of feet did not show obviousmalformations (data not shown).

Linkage of the Two Chinese SYM1 Families tothe GDF5 Gene on Chromosome 20q11.21-q12

Linkage analysis with markers D17S1868 andD17S787 excluded the NOG gene as the disease-causing gene in the two Chinese families with SYM1(data not shown). Genome-wide linkage analysiswith 382 markers covering chromosomes 1–22identified linkage of the disease to D20S106 andD20S909 in both families with a combined LODscore of>3.0 at a recombination fraction of 0 (see theonline Tables IV and V at http://www.interscience.wiley.com/jpages/1552-4825/suppmat/index.htmland Fig. 3). Haplotype analysis revealed that the

FIG. 1. Radiographic features of thehands and feet of SYM1patients associatedwith the E491KmutationofGDF5.A:Osseous fusion of 2–4proximal interphalangealjoints. Note also the fusion of distal interphalangeal joints in the fifth digits of both hands and the bending of fingers IV in left and right hands (clinodactyly).B: Fusion ofproximal interphalangeal joints in the 2–5digits.C: Phenotypeof the left foot. Note that the second and the third cuneiform bones were fused to the secondand the thirdmetatarsus bones, respectively, and the absence of the cuboid bone and the fusion between scaphoid and talus. D: Phenotype of the right foot. Note the bony fusionbetween the second cuneiform bone and the third cuneiform bones, and the absence of the cuboid bone and the fusion between scaphoid and talus. E: Flat footassociated with the GDF5 E491K mutation.

FIG. 2. The radiography of the hands from a young patient in Family 1(individual V:2). Note the obvious tendency of interphalangeal joint osseousfusions of the 4th–5th fingers in both hands. The gaps between the distal end ofthe proximal phalanx and the proximal end of the middle phalanx turned out tobe much narrower than other normal gaps.



FIG. 3. Genetic linkageof twoChinese familieswith SYM1 to chromosome20q11.21-q12.A: Thepedigree structure of Family 1.B: Thepedigree structure of Family 2.Genotype results for markersD20S112,D20S195,D20S106,D20S909,D20S107, andD20S119 are shown below each symbol. The haplotype cosegregating with thedisease is indicated by a black vertical bar.

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disease-causing gene is localized between D20S195andD20S107 (Fig. 3A,B). The affected individuals inthe two families showed the identical haplotype of 1-3-3-5-1-4, which suggests that the two families sharethe same ancestor. This is consistent with the findingthat the two families live in the same geographicregion of Guilin, Guangxi province of China andshared the same ancestor based on a family historyinvestigation.

GDF5 Mutation E491K is Associated WithSYM1 in Two Chinese Families

As the GDF5 gene is located between markersD20S106 and D20S909, the two markers linked to

the two Chinese SYM1 families, mutation analysiswas performed in this gene. One heterozygous G-to-A transition was found at nucleotide 1,471 in exon 2of GDF5 (NM 000557) by direct DNA sequenceanalysis (Fig. 4A,B). The G-to-A transition resultsin the substitution of a negatively charged glutamicacid residue for an electropositive lysine residue(E491K) in the TGF-b domain. The alignment ofamino acids of TGF-b domains from Zebrafish,Xenopus laevis, to humans (Homo sapiens) showedthat the residue E491 of GDF5 is evolutionallyconserved among different species (Fig. 4E). Thisnovel E491K mutation is located in a critical regionofGDF5 that serves as the biologically activedomain.Mutation E491K is located within the receptor I

FIG. 4. Identification of the E491Kmutation inGDF5 that is associated with SYM1 in two Chinese families.A: Sequence chromatogram of a unaffected family member(II:7) in Family 1. B: Sequence analysis of exon 2 of GDF5 in the proband (III:4) in Family 1. The mutation is indicated by an arrow. The mutation is a transition ofc.1471G>A (p.E491K). The G to A transition results in the substitution of a negatively charged glutamic acid residue for an electropositive lysine residue (E491K) in theTGF-b domain. The same mutation was also identified in the proband of Family 2 (data not shown).C,D: SSCP analyses of Family 1 (C) and Family 2 (D). The abnormalSSCP bands are shown by arrows. N, normal phenotype; P, affected phenotype. E: Alignment of the amino acid sequences of TGF-b domains in GDF5 from differentspecies. The conserved amino acid residues where the mutations occur are boxed. The mutations in the TGF-b domain of GDF5 associated with human disease areindicated: heterozygous mutation E491K associated with SYM1 identified in this study (denoted by double asterisks), R438L associated with SYNS1, SYM1 (denoted by asingle asterisk), R438C and C498S associated with BDC, R438C associated with CVT, L441P associated with BDA2, homozygous mutation L441P associated with DuPansyndrome, C400Y associated with CGT, and 1475ins22 associated with CHTT.



and noggin interaction site of TGF-b domain asdeduced from the alignment of the GDF5 sequencewith three TGF superfamily members BMP2, BMP7,and TGFb2 with known crystal structures [Schreuderet al., 2005].

SSCP analysis showed that the GDF5 mutation co-segregated with all affected individuals in Family 1(Fig. 4C) and Family 2 (Fig. 4D). The mutation wasnot present in 200 healthy Chinese controls. Theseresults suggest that the E491K mutation does notrepresent a rare polymorphism, but is a causativemutation for the autosomal dominant SYM1 in thetwo Chinese families.

DISCUSSION

In this study, we identified a novel mutation,E491K, in the GDF5 gene in two five-generationChinese families with SYM1. The GDF5 mutation co-segregates with the disease in the two families with atotal of 13 patients, and does not exist in 200 controls.The E491 residue is highly conserved from Zebrafishto humans in GDF5. These results support theconclusion that mutation E491K is a disease-causingmutation for SYM1. Mutation E491K represents thefirst novel GDF5 mutation identified in a Chinesepopulation, and only the second GDF5 mutationidentified for SYM1 to date. The mutation is alsoassociated with some unique clinical features. Thepatients in the two Chinese families have someclinical features that are not present in patients withGDF5 mutation R438L: the absence of cuboid bone,the presence of distal interphalangeal joint fusions,andflat feet. Thepatients in this study also have somefeatures that SYM1patientswithnogginmutations donot have, that is, the lack of shortness of the first andfifth metacarpal bones [Gong et al., 1999]. Further-more, patients with mutation R438L have broadhemicylindrical nose, vertebral fusions [Dawsonet al., 2006], which are not present in the patientscarrying mutation E491K. It is important to note thatthe patientswith mutations R438L and E491K all haveprogressive SYM1, osseous fusion of interphalangealjoints of fingers, and carpal, tarsal fusions [Dawsonet al., 2006 and this study].

In the two Chinese families studied here, thefeature of interphalangeal joints osseous fusion ofthe 2–4 fingers (Fig. 1A) was obvious and indis-tinguishable from that observed in SYM1 individualswith NOG mutations [Gong et al., 1999] or the GDF5mutation R438L [Seemann et al., 2005]. The specificfingers affected vary in different patients. Unlike thefeatures caused by theNOGmutations, the shortnessof the first and fifth metacarpal bones and thefusion between the triquetral bone in the wrist andthe first metacarpal bone [Gong et al., 1999] were notobserved in all the patients of the two families. It isinteresting to note that the GDF5 E491K mutationresulted in both distal interphalangeal joint fusion

and proximal interphalangeal joint fusion of the fifthdigits in the affected individuals of the two families inthis study (Fig. 1A,B).

The osseous fusion of fingers in hands was theclinical feature described for patients with the GDF5mutation R438L [Seemann et al., 2005]. The carpaland tarsal fusions were later reported in patients withGDF5 mutation R438L [Dawson et al., 2006]. Thecarpal bone malformation and fusion betweentrapezium and trapezoid, and the fusion betweenthe capitate bone and hamate bone were clearlydetected in patients with mutation E491K. To SYM1,the tarsal bone coalition had been described asthe most disabling feature [Strasburger et al., 1965],which is also the feature in the two Chinese familiesin this study. But the absence of the cuboid bones is aunique clinical feature observed in both feet inseveral patients under this study. Another interestingfeature is the coalition between the cuneiform boneand metatarsus. The second and the third cuneiformbones were fused to the second and the thirdmetatarsus bones, respectively in the left foot,whereas the second cuneiform bone was fused tothe third cuneiform bone in the right foot in onepatient (Fig. 1C,D). Patients with TCC displayedvariable abnormalities of the elbow, humeroradialfusions and painful and difficult ambulation ofthe ankle and foot [Dixon et al., 2001], but theseabnormalities were not present in the two Chinesefamilies in this study. Patients with the GDF5mutation R438L showed the broad hemicylindricalnose and vertebral fusions [Dawson et al., 2006],however, these features were not present in theChinese patients with mutation E491K.

Although clinical features were variable in affectedindividuals, either interfamily or intrafamily, pene-trance of the E491K mutation of GDF5 was completein all the male and female patients. The fusions andmalformations turned out to be more severe with theincreasing age. The younger patients had only thetendency of fusions in hands and no obviousmalformations in wrist and feet, whereas the olderones had clear abnormalities in both hands and feet.This is similar to the TCC phenotype caused by NOGmutations, in which only after birth does theprogressive fusion of the proximal interphalangealjoints of digits 4, 3, and 2 proceed [Dixon et al.,2001].

For disorders associated with GDF5 mutations,the autosomal recessive disorders were more severethan autosomal dominant conditions. Studies showedthat CHTT could be caused by the absence of GDF5[Thomas et al., 1996]. GDF5 lost biologically activityby compound heterozygous mutations, one C400Ymutation and the other for a deletion of a G nucleo-tide in the CGT patients [Thomas et al., 1997]. SomeGDF5 mutations could result in haploinsufficiencyand producedistinct mild phenotypes [Thomas et al.,1997]. To BDC, the expression data in vitro suggested

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functional haploinsufficiency as the main effect ofthe mutations [Everman et al., 2002].

GDF5 binds to type I-receptors (e.g., BMPR1A) ortype II-receptors (e.g., AMHR2) to execute itsfunctions [Schreuder et al., 2005]. Both E491K andR438L mutations are located within the interactionsite with type I receptors and noggin (an antagonistofGDF5) [Schreuder et al., 2005]. BothE491 andR438residues are conserved among different species(Fig. 4E). The R438L mutation is a gain-of-functionmutation that results in a GDF5 with BMP2-likeproperties and alters binding affinities for BMPR1A,but does not change the GDF5 binding to noggin andthe type II receptor [Seemann et al., 2005]. The E491Kmutation may act by a similar mechanism to theR438Lmutation as they are only 53 amino acids apart.

ACKNOWLEDGMENTS

We thank all members of the families for theirsupport of this research. This study would beimpossible without their enthusiastic participation.The authors also acknowledge SusanDe Stenfano forher help with the manuscript. This work wassupported by the Tenth ‘‘Five-Year’’ National Scienceand Technology Key Program of China grant No.2004BA720A (to M.L.), the National Natural ScienceFoundation of China No. 30470982, and the ChineseMinistry of Science and Technology National HighTechnology ‘‘863’’ Programs of China No. 2002BA711A07 (to Q.K.W.). Q.K.W. is an EstablishedInvestigator of the American Heart Association.

REFERENCES

Brown DJ, Kim TB, Petty EM, Downs CA, Martin DM, Strouse PJ,Moroi SE, Milunsky JM, Lesperance MM. 2002. Autosomaldominant stapes ankylosis with broad thumbs and toes,hyperopia, and skeletal anomalies is caused by heterozygousnonsense and frameshift mutations in NOG, the geneencoding noggin. Am J Hum Genet 71:618–624.

Chen Q, Kirsch GE, Zhang D, Brugada R, Brugada J, Brugada P,Potenza D, Moya A, Borggrefe M, Breithardt G, Ortiz-Lopez R,Wang Z, Antzelevitch C, O’Brien RE, Schulze-Bahr E, KeatingMT, Towbin JA, Wang Q. 1998. Genetic basis and molecularmechanism for idiopathic ventricular fibrillation. Nature392:293–296.

Cushing H. 1916. Hereditary anchylosis of proximal phalangealjoints (symphalangism). Genetics 1:90–106.

Dawson K, Seeman P, Sebald E, King L, Edwards M, Williams J III,Mundlos S, Krakow D. 2006. GDF5 is a second locus formultiple-synostosis syndrome. Am J Hum Genet 78:708–712.

Dixon ME, Armstrong P, Stevens DB, Bamshad M. 2001. Identicalmutations in NOG can cause either tarsal/carpal coalition syn-drome or proximal symphalangism. Genet Med 3:349–353.

Dobbs MB, Gurnett CA, Robarge J, Gordon JE, Morcuende JA,Bowcock AM. 2005. Variable hand and foot abnormalities infamily with congenital vertical talus and CDMP-1 genemutation. J Orthop Res 23:1490–1494.

Everman DB, Bartels CF, Yang Y, Yanamandra N, Goodman FR,Mendoza-Londono JR, Savarirayan R, White SM, Graham JM

Jr, Gale RP, Svarch E, Newman WG, Kleckers AR, FrancomanoCA, Gocindaiah V, Singh L, Morrison S, Thomas JT, WarmanML. 2002. The mutational spectrum of brachydactyly type C.Am J Med Genet 112:291–296.

Faiyaz-Ul-Haque M, Ahmad W, Wahab A, Haque S, Azim AC,Zaidi SHE, Teebi AS, Ahmad M, Cohn DH, Siddique T, Tsui LC.2002a. Frameshift mutation in the cartilage-derived morpho-genetic protein 1 (CDMP1) gene and severe acromesomelicchondrodysplasia resembling Grebe-type chondrodysplasia.Am J Med Genet 111:31–37.

Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Haque S, Teebi AS,Ahmad M, Cohn DH, Tsui LC. 2002b. Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindredaffected with fibular hypoplasia and complex brachydactyly(DuPan syndrome). Clin Genet 61:454–458.

Gong Y, Krakow D, Marcelino J, Wilkin D, Chitayat D, Babul-HirjiR, Hudgins L, Cremers CW, Cremers FP, Brunner HG, ReinkerK, Rimoin DL, Cohn DH, Goodman FR, Reardon W, Patton M,Francomano CA, Warman ML. 1999. Heterozygous mutationsin the gene encoding noggin affect human joint morphogen-esis. Nat Genet 21:302–304.

Polinkovsky A, Robin NH, Thomas JT, Irons M, Lynn A, GoodmanFR, Reardon W, Kant SG, Brunner HG, van der Burgt I,Chitayat D, McGaughran J, Donnai D, Luyten FP, Warman ML.1997. Mutations in CDMP1 cause autosomal dominantbrachydactyly type C. Nat Genet 17:18–19.

Savarirayan R, White SM, Goodman FR, Graham JM, DelatyckiMB, Lachman RS, Rimoin DL, Everman DB, Warman ML. 2003.Broad phenotypic spectrum caused by an identical hetero-zygous CDMP-1 mutation in three unrelated families. Am JMed Genet Part A 117A:136–142.

Schreuder H, Liesum A, Pohl J, Kruse M, Koyama M. 2005. Crystalstructure of recombinant human growth and differentiationfactor 5: Evidence for interaction of the type I and type IIreceptor-binding sites. Biochem Biophys Res Commun 329:1076–1086.

Schwabe GC, Turkmen S, Leschik G, Palanduz S, Stover B,Goecke TO, Mundlos S. 2004. Brachydactyly type C caused bya homozygous missense mutation in the prodomain ofCDMP1. Am J Med Genet Part A 124A:356–363.

Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K,Dawson K, Stricker S, Pohl J, Ploger F, Staub E, Nickel J, SebaldW, Knaus P, Mundlos S. 2005. Activating and deactivatingmutations in the receptor interaction site of GDF5 causesymphalangism or brachydactyly type A2. J Clin Invest115:2373–2381.

Strasburger AK, Hawkins MR, Eldridge R, Hargrave RL, McKusickVA. 1965. Symphalangism: Genetic and clinical aspects. BullJohns Hopkins Hosp 117:108–127.

Takahashi T, Takahashi I, Komatsu M, Sawaishi Y, Higashi K,Nishimura G, Saito H, Takada G. 2001. Mutations of the NOGgene in individuals with proximal symphalangism and multi-ple synostosis syndrome. Clin Genet 60:447–451.

Thomas JT, Lin K, Nandekar M, Camargo M, Cervenka J, LuytenFP. 1996. A human chondrodysplasia due to a mutation in aTGF-beta superfamily member. Nat Genet 12:315–317.

Thomas JT,KilpatrickMW, LinK, Erlacher L, Lembessis P, Costa T,Tsipouras P, Luyten FP. 1997. Disruption of human limbmorphogenesis by a dominant negative mutation in CDMP1.Nat Genet 17:58–64.

Wang Q, Liu M, Xu C, Tang Z, Liao Y, Du R, Li W, Wu X, Wang X,Liu P, Zhang X, Zhu J, Ren X, Ke T, Wang Q, Yang J. 2005.Novel CACNA1S mutation causes autosomal dominanthypokalemic periodic paralysis in a Chinese family. J MolMed 83:203–208.

Zimmerman LB, De Jesus-Escobar JM, Harland RM. 1996. TheSpemann organizer signal noggin binds and inactivates bonemorphogenetic protein 4. Cell 86:599–606.



a novel mutation in gdf5 causes autosomal dominant symphalangism in two chinese families

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