Background: We wishg to generalize our ability to measure candidate human allele functionality in zebrafish, with the sole requirements being that the gene in question is sufficiently analogous to a zebrafish gene with embryonic activity. For this we have pioneered a new platform, Nanostring, to count and correlate the quantity of injected WT and candidate mutant alleles of human RNAs with the output (activation or repression ) of a signature subset of zebrafish genes. We have applied this to two test scenarios, both in the sonic hedgehog signaling pathway: human SHH alleles and human GLI2 alleles. The results re good and we are preparing manuscripts to report upon this method and our new data.

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National Human Genome Research Institute
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Pei, Wuhong; Kratz, Lisa E; Bernardini, Isa et al. (2010) A model of Costeff Syndrome reveals metabolic and protective functions of mitochondrial OPA3. Development 137:2587-96
Huizing, Marjan; Dorward, Heidi; Ly, Lien et al. (2010) OPA3, mutated in 3-methylglutaconic aciduria type III, encodes two transcripts targeted primarily to mitochondria. Mol Genet Metab 100:149-54
Pei, Wuhong; Feldman, Benjamin (2009) Identification of common and unique modifiers of zebrafish midline bifurcation and cyclopia. Dev Biol 326:201-11
Roessler, Erich; Pei, Wuhong; Ouspenskaia, Maia V et al. (2009) Cumulative ligand activity of NODAL mutations and modifiers are linked to human heart defects and holoprosencephaly. Mol Genet Metab 98:225-34
Domene, Sabina; Roessler, Erich; El-Jaick, Kenia B et al. (2008) Mutations in the human SIX3 gene in holoprosencephaly are loss of function. Hum Mol Genet 17:3919-28
Roessler, Erich; Ouspenskaia, Maia V; Karkera, Jayaprakash D et al. (2008) Reduced NODAL signaling strength via mutation of several pathway members including FOXH1 is linked to human heart defects and holoprosencephaly. Am J Hum Genet 83:18-29