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Structural highlights

Disease

[GDF5_HUMAN] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Grebe type (AMDG) [MIM:200700]. Acromesomelic chondrodysplasias are rare hereditary skeletal disorders characterized by short stature, very short limbs, and hand/foot malformations. The severity of limb abnormalities increases from proximal to distal with profoundly affected hands and feet showing brachydactyly and/or rudimentary fingers (knob-like fingers). AMDG is an autosomal recessive form characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet.^[1] Defects in GDF5 are the cause of acromesomelic chondrodysplasia Hunter-Thompson type (AMDH) [MIM:201250]. AMDH is an autosomal recessive form of dwarfism. Patients have limb abnormalities, with the middle and distal segments being most affected and the lower limbs more affected than the upper. AMDH is characterized by normal axial skeletons and missing or fused skeletal elements within the hands and feet. Defects in GDF5 are the cause of brachydactyly type C (BDC) [MIM:113100]. BDC is an autosomal dominant disorder characterized by an abnormal shortness of the fingers and toes. Note=Some BDC patients with GDF5 mutations also manifest clinical features of ASPED angel-shaped phalango-epiphyseal dysplasia (ASPED), an autosomal dominant skeletal abnormality characterized by a typical angel-shaped phalanx, brachydactyly, specific radiological findings, abnormal dentition, hip dysplasia, and delayed bone age. This suggests that BDC and ASPED are part of the same clinical spectrum (PubMed:22828468).^{[2] [3]} Defects in GDF5 are the cause of Du Pan syndrome (DPS) [MIM:228900]; also known as fibular hypoplasia and complex brachydactyly. Du Pan syndrome is a rare autosomal recessive condition characterized by absence of the fibulae and severe acromesomelic limb shortening with small, non-functional toes. Although milder, the phenotype resembles the autosomal recessive Hunter-Thompson and Grebe types of acromesomelic chondrodysplasia.^{[4] [5] [6]} Defects in GDF5 are a cause of symphalangism proximal syndrome (SYM1) [MIM:185800]. SYM1 is characterized by the hereditary absence of the proximal interphalangeal (PIP) joints (Cushing symphalangism). Severity of PIP joint involvement diminishes towards the radial side. Distal interphalangeal joints are less frequently involved and metacarpophalangeal joints are rarely affected whereas carpal bone malformation and fusion are common. In the lower extremities, tarsal bone coalition is common. Conducive hearing loss is seen and is due to fusion of the stapes to the petrous part of the temporal bone.^{[7] [8] [9]} Defects in GDF5 are the cause of multiple synostoses syndrome type 2 (SYNS2) [MIM:610017]. Multiple synostoses syndrome is an autosomal dominant condition characterized by progressive joint fusions of the fingers, wrists, ankles and cervical spine, characteristic facies and progressive conductive deafness.[:]^[10] Defects in GDF5 are a cause of brachydactyly type A2 (BDA2) [MIM:112600]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.^{[11] [12]} Genetic variations in GDF5 are associated with susceptibility to osteoarthritis type 5 (OS5) [MIM:612400]. Osteoarthritis is a degenerative disease of the joints characterized by degradation of the hyaline articular cartilage and remodeling of the subchondral bone with sclerosis. Clinical symptoms include pain and joint stiffness often leading to significant disability and joint replacement. Defects in GDF5 may be a cause of brachydactyly type A1 (BDA1) [MIM:112500]. Brachydactylies (BDs) are a group of inherited malformations characterized by shortening of the digits due to abnormal development of the phalanges and/or the metacarpals. They have been classified on an anatomic and genetic basis into five groups, A to E, including three subgroups (A1 to A3) that usually manifest as autosomal dominant traits.^[13]

Function

[GDF5_HUMAN] Could be involved in bone and cartilage formation. Chondrogenic signaling is mediated by the high-affinity receptor BMPR1B.^{[14] [15]}

References

1. ↑ Thomas JT, Kilpatrick MW, Lin K, Erlacher L, Lembessis P, Costa T, Tsipouras P, Luyten FP. Disruption of human limb morphogenesis by a dominant negative mutation in CDMP1. Nat Genet. 1997 Sep;17(1):58-64. PMID:9288098 doi:10.1038/ng0997-58
2. ↑ Gutierrez-Amavizca BE, Brambila-Tapia AJ, Juarez-Vazquez CI, Holder-Espinasse M, Manouvrier-Hanu S, Escande F, Barros-Nunez P. A novel mutation in CDMP1 causes brachydactyly type C with "angel-shaped phalanx". A genotype-phenotype correlation in the mutational spectrum. Eur J Med Genet. 2012 Nov;55(11):611-4. doi: 10.1016/j.ejmg.2012.07.004. Epub, 2012 Jul 22. PMID:22828468 doi:10.1016/j.ejmg.2012.07.004
3. ↑ Schwabe GC, Turkmen S, Leschik G, Palanduz S, Stover B, Goecke TO, Mundlos S. Brachydactyly type C caused by a homozygous missense mutation in the prodomain of CDMP1. Am J Med Genet A. 2004 Feb 1;124A(4):356-63. PMID:14735582 doi:10.1002/ajmg.a.20349
4. ↑ Faiyaz-Ul-Haque M, Ahmad W, Zaidi SH, Haque S, Teebi AS, Ahmad M, Cohn DH, Tsui LC. Mutation in the cartilage-derived morphogenetic protein-1 (CDMP1) gene in a kindred affected with fibular hypoplasia and complex brachydactyly (DuPan syndrome). Clin Genet. 2002 Jun;61(6):454-8. PMID:12121354
5. ↑ Szczaluba K, Hilbert K, Obersztyn E, Zabel B, Mazurczak T, Kozlowski K. Du Pan syndrome phenotype caused by heterozygous pathogenic mutations in CDMP1 gene. Am J Med Genet A. 2005 Nov 1;138(4):379-83. PMID:16222676 doi:10.1002/ajmg.a.30969
6. ↑ Douzgou S, Lehmann K, Mingarelli R, Mundlos S, Dallapiccola B. Compound heterozygosity for GDF5 in Du Pan type chondrodysplasia. Am J Med Genet A. 2008 Aug 15;146A(16):2116-21. doi: 10.1002/ajmg.a.32435. PMID:18629880 doi:10.1002/ajmg.a.32435
7. ↑ Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Ploger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S. Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest. 2005 Sep;115(9):2373-81. Epub 2005 Aug 25. PMID:16127465 doi:10.1172/JCI25118
8. ↑ Wang X, Xiao F, Yang Q, Liang B, Tang Z, Jiang L, Zhu Q, Chang W, Jiang J, Jiang C, Ren X, Liu JY, Wang QK, Liu M. A novel mutation in GDF5 causes autosomal dominant symphalangism in two Chinese families. Am J Med Genet A. 2006 Sep 1;140A(17):1846-53. PMID:16892395 doi:10.1002/ajmg.a.31372
9. ↑ Yang W, Cao L, Liu W, Jiang L, Sun M, Zhang D, Wang S, Lo WH, Luo Y, Zhang X. Novel point mutations in GDF5 associated with two distinct limb malformations in Chinese: brachydactyly type C and proximal symphalangism. J Hum Genet. 2008;53(4):368-74. Epub 2008 Feb 19. PMID:18283415 doi:10.1007/s10038-008-0253-7
10. ↑ Dawson K, Seeman P, Sebald E, King L, Edwards M, Williams J 3rd, Mundlos S, Krakow D. GDF5 is a second locus for multiple-synostosis syndrome. Am J Hum Genet. 2006 Apr;78(4):708-12. Epub 2006 Feb 24. PMID:16532400 doi:10.1086/503204
11. ↑ Seemann P, Schwappacher R, Kjaer KW, Krakow D, Lehmann K, Dawson K, Stricker S, Pohl J, Ploger F, Staub E, Nickel J, Sebald W, Knaus P, Mundlos S. Activating and deactivating mutations in the receptor interaction site of GDF5 cause symphalangism or brachydactyly type A2. J Clin Invest. 2005 Sep;115(9):2373-81. Epub 2005 Aug 25. PMID:16127465 doi:10.1172/JCI25118
12. ↑ Ploger F, Seemann P, Schmidt-von Kegler M, Lehmann K, Seidel J, Kjaer KW, Pohl J, Mundlos S. Brachydactyly type A2 associated with a defect in proGDF5 processing. Hum Mol Genet. 2008 May 1;17(9):1222-33. doi: 10.1093/hmg/ddn012. Epub 2008 Jan, 18. PMID:18203755 doi:10.1093/hmg/ddn012
13. ↑ Byrnes AM, Racacho L, Nikkel SM, Xiao F, MacDonald H, Underhill TM, Bulman DE. Mutations in GDF5 presenting as semidominant brachydactyly A1. Hum Mutat. 2010 Oct;31(10):1155-62. doi: 10.1002/humu.21338. PMID:20683927 doi:10.1002/humu.21338
14. ↑ Bai X, Xiao Z, Pan Y, Hu J, Pohl J, Wen J, Li L. Cartilage-derived morphogenetic protein-1 promotes the differentiation of mesenchymal stem cells into chondrocytes. Biochem Biophys Res Commun. 2004 Dec 10;325(2):453-60. PMID:15530414 doi:10.1016/j.bbrc.2004.10.055
15. ↑ Kotzsch A, Nickel J, Seher A, Sebald W, Muller TD. Crystal structure analysis reveals a spring-loaded latch as molecular mechanism for GDF-5-type I receptor specificity. EMBO J. 2009 Apr 8;28(7):937-47. Epub 2009 Feb 19. PMID:19229295 doi:10.1038/emboj.2009.37
16. ↑ Gigout A, Werkmann D, Menges S, Brenneis C, Henson F, Cowan KJ, Musil D, Thudium CS, Guhring H, Michaelis M, Kleinschmidt-Doerr K. R399E, a mutated form of Growth and Differentiation Factor 5, for disease modification of osteoarthritis. Arthritis Rheumatol. 2022 Sep 2. doi: 10.1002/art.42343. PMID:36054172 doi:http://dx.doi.org/10.1002/art.42343