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Evaluation of the ELOVL4 gene in families with retinitis pigmentosa linked to theRP25 locus

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Editor—Retinitis pigmentosa (RP) is the most common form of retinal dystrophy. Patients present with night blindness and progressive narrowing of the visual field, eventually leading to central vision loss. Fundus examination usually shows bone spicula pigmentation, attenuation of blood vessels in the retina, and waxy pallor of the optic disc. Typically, the electroretinogram is notably diminished or even abolished.1

RP shows important allelic and non-allelic genetic heterogeneity (RET-GEN-NET) with different modes of inheritance, including autosomal dominant (AD), autosomal recessive (AR), X linked, and digenic.

ARRP is the most common form of RP. A locus for ARRP,RP25, was mapped in 1998 to the long arm of chromosome 6 between microsatellite markers D6S257 and D6S1644 (MIM 602772).2 Recently, we have excluded two candidates,GABRR1 and GABRR2,as the disease causing gene.3

Several loci with retinal dystrophy phenotypes have been mapped to the pericentromeric region of chromosome 6. They include autosomal dominant Stargardt-like disease (STGD3),4 autosomal dominant macular atrophy (ADMD),5autosomal dominant cone-rod dystrophy (CORD7),6 and Leber congenital amaurosis (LCA5).7

Recently, the gene responsible for STGD3 andADMD has been identified.8 All affected members in four independent families with STGD3 and one family with ADMD shared a common founder haplotype, indicating a single ancestral disease specific mutation. A single 5 bp deletion of a novel gene called ELOVL4 was identified, which segregates with all affected members of the STGD3 and ADMD families.ELOVL4 shows cone and rod photoreceptor expression in the eye, is composed of six exons, and encodes a putative transmembrane protein of 314aa with similarities to the ELO family of proteins involved in elongation of very long chain fatty acids. Based on its similarity, it has been suggested that this protein is involved in synthesis of polyunsaturated fatty acids (PUFA) in the retina, such as DHA (docosahexaenoic acid). DHA represents 50% of PUFA in the outer segment of the photoreceptor cells and plays a crucial role in photoreceptor cell functions.

It is well known that one gene can cause distinct disease phenotypes with retinal degeneration.9-19 For example,ABCR (also calledABCA4), the gene responsible for recessive Stargardt macular dystrophy (STGD1), can cause either ARRP or autosomal recessive cone-rod dystrophy.17 20-23

It has been known for a long time that the retina possesses unique properties in lipid metabolism. The high level of PUFA, such as DHA, in the photoreceptors is thought to form an essential lipid environment for the phototransduction function. In addition, DHA is known to be lower in the serum of patients with retinitis pigmentosa. This evidence suggests that lipid metabolism may play a role in the pathogenesis of RP.24-28

ELOVL4 maps within the criticalRP25 region and has a potential role in DHA synthesis. We therefore considered ELOVL4 to be a good candidate for the RP25 gene and performed mutational analysis of ELOVL4 in RP families linked to this locus. Eight families with 18 patients were included in these studies.

Each exon of the ELOVL4 gene was amplified from genomic DNA derived from the index patients of the eight families using intronic primers (table 1). These PCR products were purified, analysed by EMD (enzymatic mutation detection),29 and automatically sequenced as previously described.3

Table 1

PCR amplification of individual exons of the ELOVL4 gene

Only two heterozygous variations were identified, both of which (IVS2-99T→C and M299V) have been previously described by Zhanget al 8 as non-pathogenic polymorphisms. These variants have been found in one family linked toRP25. In this particular family, there are two patients, both heterozygous for IVS2-99T→C and M299V. However, we did not detect any pathogenic variation in theELOVL4 gene in the RP patients. Therefore, we excluded ELOVL4 as the gene responsible for RP25. Thus, our data indicate that at least two different genes involved in retinal degeneration are located in this region of the long arm of chromosome 6.

In conclusion, we have conducted a mutational screen inELOVL4, the gene responsible for STGD3 and ADMD in ARRP families linked to RP25. After direct molecular analysis of the coding sequence and the intron-exon boundaries of ELOVL4, we did not find any pathogenic variant. Our results indicate that theELOVL4 gene seems not to be involved in the pathogenesis of RP25 andSTGD3/ADMDand RP25 are not allelic variants of the same gene. Nevertheless, a role forELOVL4 in other inherited forms of RP needs to be elucidated.


Data access: RET-GEN-NET, Online Mendelian Inherited in Man (OMIN), http://www.ncbi.nlm.nih/htbin-post/OMIN

The first two authors contributed equally to this work. We would like to express our gratitude to all those affected by RP for their cooperation, essential for the completion of this study. This study was supported by Helen Keller Eye Research Foundation (YL), Grant Ritter Fund and NIH EY00401 (KZ), Fondo de Investigaciones Sanitarias (99/0010-02) (SB, GA), the Fundación ONCE, and the Asociación Andaluza de Retinosis Pigmentaria. IM is recipient of a fellowship from the Instituto de Salud Carlos III (99/4250, Ministerio de Sanidad y Consumo, Spain).


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