A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families.
Proximal symphalangism (SYM1) is an autosomal dominant disorder characterized by ankylosis of the proximal interphalangeal joints and fusion of carpal and tarsal bones. We identified and characterized two five-generation Chinese families 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 NOG gene or the family with mutation R438L recently reported in the GDF5 gene (encoding a bone morphogenetic protein family member). However, they show some unique features including the absence of cuboid bone, the lack of shortness of the first and fifth metacarpal bones, and manifestation of flat feet. Genome-wide linkage analysis of the two families mapped the disease gene to marker D20S112 with a 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 the TGF-beta domain of GDF5 and represents the second GDF5 mutation identified for SYM1 to date. The E491K mutation co-segregated with the affected individuals in the two families, and did not exist in unaffected family members or 200 normal controls. These results indicate that defects in GDF5 can cause SYM1 in the Chinese population, and expand the spectrum of clinical phenotypes associated with mutant GDF5.
Wang
Xu
X
Human Genome Research Center and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, P. R. China.
Xiao
Fuying
F
Yang
Qinbo
Q
Liang
Bo
B
Tang
Zhaohui
Z
Jiang
Linbin
L
Zhu
Qihui
Q
Chang
Wei
W
Jiang
Jiuxi
J
Jiang
Chuanming
C
Ren
Xiang
X
Liu
Jing-Yu
JY
Wang
Qing K
QK
Liu
Mugen
M
D000595:Amino Acid Sequence; D000844:Ankylosis / Q000175:diagnosis / Q000235:genetics*; D044466:Asian People; D019485:Bone Morphogenetic Proteins / Q000235:genetics*; D002352:Carrier Proteins / Q000235:genetics; D004252:DNA Mutational Analysis; D005190:Family; D005384:Finger Joint / Q000002:abnormalities*; D005799:Genes, Dominant; D008040:Genetic Linkage; D055428:Growth Differentiation Factor 5; D006801:Humans; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D014033:Toe Joint / Q000002:abnormalities*; D000099176:Noggin Protein
D019485:Bone Morphogenetic Proteins; D002352:Carrier Proteins; D055428:Growth Differentiation Factor 5; D000099176:Noggin Protein; C525893:GDF5 protein, human