High Temperature Requirement Factor A1 (HTRA1) Gene Regulates Angiogenesis through Transforming Growth Factor- Family Member Growth Differentiation Factor 6

Molecular Medicine Research Center and Department of Ophthalmology, West China Hospital, Sichuan University, Chengdu 610041, China.
Journal of Biological Chemistry (Impact Factor: 4.57). 11/2011; 287(2):1520-6. DOI: 10.1074/jbc.M111.275990
Source: PubMed


Genome-wide association study (GWAS) has identified genetic variants in the promoter region of the high temperature requirement factor A1 (HTRA1) gene associated with age-related macular degeneration (AMD). As a secreted serine protease, HTRA1 has been reported to interact with members of the transforming growth factor-β (TGF-β) family and regulate their signaling pathways. Growth differentiation factor 6 (GDF6), a member of the TGF-β family, is involved in ectoderm patterning and eye development. Mutations in GDF6 have been associated with abnormal eye development that may result in microphthalmia and anophthalmia. In this report, we identified a single nucleotide polymorphism (SNP) rs6982567 A/G near the GDF6 gene that is significantly associated with AMD (p value = 3.54 × 10(-8)). We demonstrated that the GDF6 AMD risk allele (rs6982567 A) is associated with decreased expression of the GDF6 and increased expression of HTRA1. Similarly, the HTRA1 AMD risk allele (rs10490924 T) is associated with decreased GDF6 and increased HTRA1 expression. We observed decreased vascular development in the retina and significant up-regulation of GDF6 gene in the RPE layer, retinal and brain tissues in HTRA1 knock-out (htra1(-/-)) mice as compared with the wild-type counterparts. Furthermore, we showed enhanced SMAD signaling in htra1(-/-) mice. Our data suggests a critical role of HTRA1 in the regulation of angiogenesis via TGF-β signaling and identified GDF6 as a novel disease gene for AMD.

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    • "Mutations in GDF6 were recently found to be associated with age-related macular degeneration and Leber's congenital amaurosis, both representing photoreceptor degenerative disease [43], [44]. Further, we demonstrated that the retinas of zebrafish gdf6as327/s327 mutants exhibit photoreceptor deficits [43], together indicating that disruption of GDF6 leads to photoreceptor degeneration, which marks gdf6a as a potential regulatory factor in the differentiation and/or maintenance of cone photoreceptors. "
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    • "Further, gdf6a loss of function accelerated disease progression in a zebrafish model of ALS. The synthesis of this data combines with recent reports of a role for GDF6 in congenital and late-onset photoreceptor degenerations [34], [53] to compel a role for GDF6 as a modifier gene in the etiology of disparate neuropathies. "
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    PLoS ONE 02/2014; 9(2):e89183. DOI:10.1371/journal.pone.0089183 · 3.23 Impact Factor
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    • "Total RNA extraction from mouse tissues or human lymphoblastoid cells, cDNA synthesis, and qRT-PCR experiments were performed as previously described (14). Assays were performed in triplicate. "
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