26.6Future Direction: Screening Novel PSC Genes for Mutations that Cause IRDs

As mentioned above, many IRDs and related ciliopathies are caused by mutations in genes that encode components of PSCs and other cilia (Badano et al. 2006; Liu et al. 2007; Hildebrandt and Zhou 2007). While significant progress has been made in identifying IRD disease genes, the genes which harbor mutations that cause disease in approximately half of IRD patients remain to be identified (Hartong et al. 2006; Badano et al. 2006; Daiger et al. 2007; Hildebrandt and Zhou 2007). To identify the candidate disease genes for IRDs, we have initiated the screening for mutations in validated PSC genes in patients with cilia related disorders, including recessive and dominant RP, LCA, and other syndromic cilia disorders such as BBS. This work of mutation screening is being performed in collaboration with several other investigators. For future studies, we will continue testing the hypothesis that genes that encode novel PSC proteins are good candidate disease genes for IRDs and related ciliopathies. We are optimistic that continued screening of validated PSC genes for mutations in patients with ciliopathies will lead to the identification of additional disease genes.

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Chapter 27

Role of Elovl4 Protein in the Biosynthesis

of Docosahexaenoic Acid

Martin-Paul Agbaga, Richard S. Brush, Md Nawajes A. Mandal, Michael H. Elliott, Muayyad R. Al-Ubaidi, and Robert E. Anderson

Abstract The disk membranes of retinal photoreceptor outer segments and other neuronal and reproductive tissues are enriched in docosahexaenoic acid (DHA, 22:6n3), which is essential for their normal function and development. The fatty acid condensing enzyme Elongation of Very Long chain fatty acids-4 (ELOVL4) is highly expressed in retina photoreceptors as well as other tissues with high 22:6n3 content. Mutations in the ELOVL4 gene are associated with autosomal dominant Stargardt-like macular dystrophy (STGD3) and results in synthesis of a truncated protein that cannot be targeted to the endoplasmic reticulum (ER), the site of fatty acid biosynthesis. Considering the abundance and essential roles of 22:6n3 in ELOVL4-expressing tissues (except the skin), it was proposed that the ELOVL4 protein may be involved in 22:6n3 biosynthesis. We tested the hypothesis that the ELOVL4 protein is involved in 22:6n3 biosynthesis by selectively silencing expression of the protein in the cone photoreceptors derived cell line 661W and showed that the ELOVL4 protein is not involved in DHA biosynthesis from the short chain fatty acid precursors 18:3n3 and 22:5n3.

27.1 Introduction

Mammalian fatty acid elongases are a group of condensing enzymes that mediate elongation of fatty acids by the addition of two carbon units of malonyl-CoA. Currently seven members of these condensing enzymes named ELOngation of Very Long chain fatty acids (ELOVL) have been reported. Their roles in fatty acid chain elongation, their fatty acid specificity, as well as the steps within the carbon chain they act on, have been studied and reviewed (Leonard et al., 2004; Meyer et al.,

M.-P. Agbaga (B)

Department of Cell Biology, Dean McGee Eye Institute, University of Oklahoma Health Sciences Center, 608 Stanton L.Young Blvd, DMEI 409, Oklahoma, OK 73104, USA

e-mail: martin-paul-agbaga@ouhsc.edu

Medicine and Biology 664, DOI 10.1007/978-1-4419-1399-9_27,C Springer Science+Business Media, LLC 2010