Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes

被引:83
作者
Asai-Coakwell, Mika [1 ]
French, Curtis R. [2 ]
Ye, Ming [1 ]
Garcha, Kamal [3 ]
Bigot, Karin [4 ]
Perera, Anoja G. [5 ]
Staehling-Hampton, Karen [5 ]
Mema, Silvina C. [1 ]
Chanda, Bhaskar [1 ]
Mushegian, Arcady [5 ]
Bamforth, Steven [6 ]
Doschak, Michael R. [7 ]
Li, Guang [7 ]
Dobbs, Matthew B. [8 ]
Giampietro, Philip F. [9 ]
Brooks, Brian P. [10 ]
Vijayalakshmi, Perumalsamy [11 ]
Sauve, Yves [1 ]
Abitbol, Marc [4 ]
Sundaresan, Periasamy [12 ]
van Heyningen, Veronica [13 ]
Pourquie, Olivier [5 ]
Underhill, T. Michael [3 ]
Waskiewicz, Andrew J. [2 ]
Lehmann, Ordan J. [1 ]
机构
[1] Univ Alberta, Dept Ophthalmol, Edmonton, AB T6G 2H7, Canada
[2] Univ Alberta, Dept Biol Sci, Edmonton, AB T6G 2E9, Canada
[3] Univ British Columbia, Dept Cell & Dev Biol, Vancouver, BC V6T 1Z3, Canada
[4] CERTO EA 2502 Minist Rech, Fac Med, F-75015 Paris, France
[5] Stowers Inst Med Res, Kansas City, MO 64110 USA
[6] Univ Alberta, Dept Med Genet, Edmonton, AB T6G 2H7, Canada
[7] Univ Alberta, Dept Pharm & Pharmaceut Sci, Edmonton, AB T6G 2H7, Canada
[8] Washington Univ, Dept Orthoped Surg, St Louis, MO 63130 USA
[9] Marshfield Clin Fdn Med Res & Educ, Dept Med Genet Serv, Marshfield, WI 54449 USA
[10] NEI, Ophthalm Genet & Visual Funct Branch, NIH, Bethesda, MD 20892 USA
[11] Aravind Eye Hosp, Dept Paediat Ophthalmol & Strabismus, Madurai, Tamil Nadu, India
[12] Aravind Med Res Fdn, Dept Genet, Madurai, Tamil Nadu, India
[13] MRC Human Genet Unit, Edinburgh EH4 2XU, Midlothian, Scotland
基金
加拿大健康研究院;
关键词
BONE MORPHOGENETIC PROTEIN; KLIPPEL-FEIL-SYNDROME; BRACHYDACTYLY TYPE A2; GROWTH-FACTOR-BETA; PREMATURE OVARIAN FAILURE; BARDET-BIEDL-SYNDROME; BMP15; GENE; ACROMESOMELIC CHONDRODYSPLASIA; DEVELOPMENTAL ANOMALIES; GERMLINE MUTATIONS;
D O I
10.1093/hmg/ddp008
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Proteins of the bone morphogenetic protein (BMP) family are known to have a role in ocular and skeletal development; however, because of their widespread expression and functional redundancy, less progress has been made identifying the roles of individual BMPs in human disease. We identified seven heterozygous mutations in growth differentiation factor 6 (GDF6), a member of the BMP family, in patients with both ocular and vertebral anomalies, characterized their effects with a SOX9-reporter assay and western analysis, and demonstrated comparable phenotypes in model organisms with reduced Gdf6 function. We observed a spectrum of ocular and skeletal anomalies in morphant zebrafish, the latter encompassing defective tail formation and altered expression of somite markers noggin1 and noggin2. Gdf6(+/-) mice exhibited variable ocular phenotypes compatible with phenotypes observed in patients and zebrafish. Key differences evident between patients and animal models included pleiotropic effects, variable expressivity and incomplete penetrance. These data establish the important role of this determinant in ocular and vertebral development, demonstrate the complex genetic inheritance of these phenotypes, and further understanding of BMP function and its contributions to human disease.
引用
收藏
页码:1110 / 1121
页数:12
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