Genetic defects of GDF6 in the zebrafish out of sight mutant and in human eye developmental anomalies

被引:38
作者
den Hollander, Anneke I. [1 ,2 ]
Biyanwila, Janisha [1 ]
Kovach, Peter [1 ]
Bardakjian, Tanya [3 ]
Traboulsi, Elias I. [4 ]
Ragge, Nicola K. [5 ,6 ]
Schneider, Adele [3 ]
Malicki, Jarema [1 ]
机构
[1] Tufts Univ, Div Craniofacial & Mol Genet, Boston, MA 02111 USA
[2] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 GA Nijmegen, Netherlands
[3] Albert Einstein Med Ctr, Philadelphia, PA 19141 USA
[4] Cleveland Clin Fdn, Ctr Genet Eye Dis, Cole Eye Inst, Cleveland, OH 44195 USA
[5] Univ Oxford, Dept Physiol Anat & Genet, Oxford OX1 3QX, England
[6] Moorfields Eye Hosp, London EC1V 2PD, England
来源
BMC GENETICS | 2010年 / 11卷
基金
美国安德鲁·梅隆基金会;
关键词
BONE MORPHOGENETIC PROTEINS; DANIO-RERIO; EMBRYONIC-DEVELOPMENT; CELL-DIFFERENTIATION; SIGNALING PATHWAYS; PATTERNING DEFECTS; COLOBOMA MAC; MUTATIONS; RETINA; ANOPHTHALMIA;
D O I
10.1186/1471-2156-11-102
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background: The size of the vertebrate eye and the retina is likely to be controlled at several stages of embryogenesis by mechanisms that affect cell cycle length as well as cell survival. A mutation in the zebrafish out of sight (out) locus results in a particularly severe reduction of eye size. The goal of this study is to characterize the out(m233) mutant, and to determine whether mutations in the out gene cause microphthalmia in humans. Results: In this study, we show that the severe reduction of eye size in the out(m233) mutant is caused by a mutation in the zebrafish gdf6a gene. Despite the small eye size, the overall retinal architecture appears largely intact, and immunohistochemical studies confirm that all major cell types are present in out(m233) retinae. Subtle cell fate and patterning changes are present predominantly in amacrine interneurons. Acridine orange and TUNEL staining reveal that the levels of apoptosis are abnormally high in out(m233) mutant eyes during early neurogenesis. Mutation analysis of the GDF6 gene in 200 patients with microphthalmia revealed amino acid substitutions in four of them. In two patients additional skeletal defects were observed. Conclusions: This study confirms the essential role of GDF6 in the regulation of vertebrate eye size. The reduced eye size in the zebrafish out(m233) mutant is likely to be caused by a transient wave of apoptosis at the onset of neurogenesis. Amino acid substitutions in GDF6 were detected in 4 (2%) of 200 patients with microphthalmia. In two patients different skeletal defects were also observed, suggesting pleitrophic effects of GDF6 variants. Parents carrying these variants are asymptomatic, suggesting that GDF6 sequence alterations are likely to contribute to the phenotype, but are not the sole cause of the disease. Variable expressivity and penetrance suggest a complex non-Mendelian inheritance pattern where other genetic factors may influence the outcome of the phenotype.
引用
收藏
页数:13
相关论文
共 57 条
[1]   Insertional mutagenesis in zebrafish identifies two novel genes, pescadillo and dead eye, essential for embryonic development [J].
Allende, ML ;
Amsterdam, A ;
Becker, T ;
Kawakami, K ;
Gaiano, N ;
Hopkins, N .
GENES & DEVELOPMENT, 1996, 10 (24) :3141-3155
[2]   GDF6, a novel locus for a spectrum of ocular developmental anomalies [J].
Asai-Coakwell, Mika ;
French, Curtis R. ;
Berry, Karyn M. ;
Ye, Ming ;
Koss, Ron ;
Somerville, Martin ;
Mueller, Rosemary ;
van Heyningen, Veronica ;
Waskiewicz, Andrew J. ;
Lehmann, Ordan J. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (02) :306-315
[3]   Incomplete penetrance and phenotypic variability characterize Gdf6-attributable oculo-skeletal phenotypes [J].
Asai-Coakwell, Mika ;
French, Curtis R. ;
Ye, Ming ;
Garcha, Kamal ;
Bigot, Karin ;
Perera, Anoja G. ;
Staehling-Hampton, Karen ;
Mema, Silvina C. ;
Chanda, Bhaskar ;
Mushegian, Arcady ;
Bamforth, Steven ;
Doschak, Michael R. ;
Li, Guang ;
Dobbs, Matthew B. ;
Giampietro, Philip F. ;
Brooks, Brian P. ;
Vijayalakshmi, Perumalsamy ;
Sauve, Yves ;
Abitbol, Marc ;
Sundaresan, Periasamy ;
van Heyningen, Veronica ;
Pourquie, Olivier ;
Underhill, T. Michael ;
Waskiewicz, Andrew J. ;
Lehmann, Ordan J. .
HUMAN MOLECULAR GENETICS, 2009, 18 (06) :1110-1121
[4]   Mutations that affect the survival of selected amacrine cell subpopulations define a new class of genetic defects in the vertebrate retina [J].
Avanesov, A ;
Dahm, R ;
Sewell, WF ;
Malicki, JJ .
DEVELOPMENTAL BIOLOGY, 2005, 285 (01) :138-155
[5]  
Avanesov A, 2004, METHOD CELL BIOL, V76, P333
[6]   Mutations in BMP4 cause eye, brain, and digit developmental anomalies:: Overlap between the BMP4 and hedgehog signaling pathways [J].
Bakrania, Preeti ;
Efthymiou, Maria ;
Klein, Johannes C. ;
Salt, Alison ;
Bunyan, David J. ;
Wyatt, Alex ;
Ponting, Chris P. ;
Martin, Angela ;
Williams, Steven ;
Lindley, Victoria ;
Gilmore, Joanne ;
Restori, Marie ;
Robson, Anthony G. ;
Neveu, Magella M. ;
Holder, Graham E. ;
Collin, J. Richard O. ;
Robinson, David O. ;
Farndon, Peter ;
Johansen-Berg, Heidi ;
Gerrelli, Dianne ;
Ragge, Nicola K. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (02) :304-319
[7]  
Crosier PS, 2002, INT J DEV BIOL, V46, P493
[8]   Development and adult morphology of the eye lens in the zebrafish [J].
Dahm, Ralf ;
Schonthaler, Helia B. ;
Soehn, Anne S. ;
Van Marle, Jan ;
Vrensen, Gijs F. J. M. .
EXPERIMENTAL EYE RESEARCH, 2007, 85 (01) :74-89
[9]   The BMP-related protein Radar:: a maintenance factor for dorsal neuroectoderm cells? [J].
Délot, E ;
Kataoka, H ;
Goutel, C ;
Yan, YL ;
Postlethwait, J ;
Wittbrodt, J ;
Rosa, FM .
MECHANISMS OF DEVELOPMENT, 1999, 85 (1-2) :15-25
[10]  
Driever W, 1996, DEVELOPMENT, V123, P37