Autosomal Dominant Stargardt-like Macular Dystrophy Research Articles

Expanding the allelic spectrum of ELOVL4-related autosomal recessive neuro-ichthyosis.

Very long-chain fatty acids (VLCFAs) composed of more than 20 carbon atoms are essential in the biosynthesis of cell membranes in the brain, skin, and retina. VLCFAs are elongated beyond 28 carbon atoms by ELOVL4 enzyme. Variants in ELOVL4 are associated with three Mendelian disorders: autosomal dominant (AD) Stargardt-like macular dystrophy type 3, AD spinocerebellar ataxia, and autosomal recessive disorder congenital ichthyosis, spastic quadriplegia and impaired intellectual development (ISQMR). Only seven subjects from five unrelated families with ISQMR have been described, all of which have biallelic single-nucleotide variants. We performed clinical exome sequencing on probands from four unrelated families with neuro-ichthyosis. We identified three novel homozygous ELOVL4 variants. Two of the families originated from the same Saudi tribe and had the exact homozygous exonic deletion in ELOVL4, while the third and fourth probands had two different novel homozygous missense variants. Seven out of the eight affected subjects had profound developmental delay, epilepsy, axial hypotonia, peripheral hypertonia, and ichthyosis. Delayed myelination and corpus callosum hypoplasia were seen in two of five subjects with brain magnetic rosonance imaging and cerebral atrophy in three. Our study expands the allelic spectrum of ELOVL4-related ISQMR. The detection of the same exonic deletion in two unrelated Saudi family from same tribe suggests a tribal founder mutation.

A novel ELOVL4 variant, L168S, causes early childhood-onset Spinocerebellar ataxia-34 and retinal dysfunction: a case report

Spinocerebellar ataxia 34 (SCA34) is an autosomal dominant inherited disease characterized by age-related cerebellar degeneration and ataxia caused by mutations in the Elongation of Very Long Chain Fatty Acid-4 (ELOVL4) gene. The ELOVL4 enzyme catalyzes the biosynthesis of both very long chain saturated fatty acids (VLC-SFA) and very long chain polyunsaturated fatty acids (VLC-PUFA) that are important for neuronal, reproductive, and skin function. Several variants in ELOVL4 have been shown to cause different tissue-specific disorders including SCA34 with or without Erythrokeratodermia Variabilis (EKV), a skin condition characterized by dry, scaly skin, Autosomal Dominant Stargardt-Like Macular Dystrophy (STGD3), and seizures associated with neuro-ichthyotic disorders. What is puzzling is how different mutations in the same gene seem to cause different tissue-specific disorders. To date, no SCA34 patients have presented with both SCA34 and STGD3 pathology that is caused by ELOVL4 variants that cause truncation of ELOVL4. Here, we report a novel case of an early childhood onset and rapidly progressive cerebellar degeneration and retinal dysfunction in a Belgian-Italian girl who developed severe dysarthria and gait problems starting at about 3.5 years of age and progressed to immobility by 4.5 years of age. Brain magnetic resonance imaging (MRI) revealed progressive vermian, cerebellar, cortical atrophy, progressive corpus callosum slimming, and hot cross bun sign visible on the MRI. Ophthalmological examinations also revealed progressive macular dysfunction as measured by electroretinography. Using exome sequencing, we identified a novel heterozygous ELOVL4 variant, c.503 T > C (p. L168S) in the patient. To understand the enzymatic function of this novel ELOVL4 variant and how it alters the levels of VLC-PUFA and VLC-SFA biosynthesis to contribute to cerebellar and retinal dysfunction, we expressed wild-type ELOVL4 or the L168S ELOVL4 variant in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. We showed that the L168S ELOVL4 variant is deficient in the biosynthesis of VLC-SFA and VLC-PUFA. Our work suggests that differential depletion of these fatty acids may be a contributing factor to the pathogenic mechanism of SCA34 with or without EKV. Further studies will help further define how the different ELOVL4 variants cause different tissue-specific disorders with variable ages of onset.

MACULAR ATROPHY AND PHENOTYPIC VARIABILITY IN AUTOSOMAL DOMINANT STARGARDT-LIKE MACULAR DYSTROPHY DUE TO PROM1 MUTATION.

To describe the phenotypic variability and rates of progression of atrophy in patients with PROM1 -associated macular dystrophy. Patients in this retrospective, longitudinal case series from a tertiary center had clinical examination and multimodal imaging performed. Areas of retinal pigment epithelium and ellipsoid zone loss over time by optical coherence tomography were calculated by two independent graders. Fifteen patients from five kindreds with an Arg373Cys mutation in PROM1 were studied. The average age was 39 years, and 80% were women. The visual acuity was 20/40 at presentation and 20/57 at last follow-up (average 4.8 years). Three distinct macular phenotypes were observed: 1) central geographic atrophy (13%), 2) multifocal geographic atrophy (20%), and 3) bull's eye maculopathy (67%). The overall rate of atrophy progression was 0.36 mm 2 /year, but the average rate of atrophy progression varied by macular phenotype: 1.08 mm 2 /year for central geographic atrophy, 0.53 mm 2 /year for multifocal geographic atrophy, and 0.23 mm 2 /year for bull's eye maculopathy. Patients with PROM1 -associated macular dystrophy demonstrate distinct phenotypes, with bull's eye maculopathy being the most common. The average rate of atrophy progression may be similar to reported rates for ABCA4 -related Stargardt disease and less than age-related macular degeneration. These results provide important measures for following treatment response in future gene and stem cell-based therapies.

ELOVL4 Mutations That Cause Spinocerebellar Ataxia-34 Differentially Alter Very Long Chain Fatty Acid Biosynthesis

The FA Elongase-4 (ELOVL4) enzyme mediates biosynthesis of both very long chain (VLC)-PUFAs and VLC-saturated FA (VLC-SFAs). VLC-PUFAs play critical roles in retina and sperm function, whereas VLC-SFAs are predominantly associated with brain function and maintenance of the skin permeability barrier. While some ELOVL4 mutations cause Autosomal Dominant Stargardt-like Macular Dystrophy (STGD3), other ELOVL4 point mutations, such as L168F and W246G, affect the brain and/or skin, leading to Spinocerebellar Ataxia-34 (SCA34) and Erythrokeratodermia variabilis. The mechanisms by which these ELOVL4 mutations alter VLC-PUFA and VLC-SFA biosynthesis to cause the different tissue-specific pathologies are not well understood. To understand how these mutations alter VLC-PUFA and VLC-SFA biosynthesis, we expressed WT-ELOVL4, L168F, and W246G ELOVL4 variants in cell culture and supplemented the cultures with VLC-PUFA or VLC-SFA precursors. Total lipids were extracted, converted to FA methyl esters, and quantified by gas chromatography. We showed that L168F and W246G mutants were capable of VLC-PUFA biosynthesis. W246G synthesized and accumulated 32:6n3, while L168F exhibited gain of function in VLC-PUFA biosynthesis as it made 38:5n3, which we did not detect in WT-ELOVL4 or W246G-expressing cells. However, compared with WT-ELOVL4, both L168F and W246G mutants were deficient in VLC-SFA biosynthesis, especially the W246G protein, which showed negligible VLC-SFA biosynthesis. These results suggest VLC-PUFA biosynthetic capabilities of L168F and W246G in the retina, which may explain the lack of retinal phenotype in SCA34. Defects in VLC-SFA biosynthesis by these variants may be a contributing factor to the pathogenic mechanism of SCA34 and Erythrokeratodermia variabilis.

Corneal involvement in a case of autosomal dominant Stargardt-like macular dystrophy (STGD3) with ELOVL4 mutation

Stargardt-like macular dystrophy (STGD3) represents an early onset, autosomal dominant form of macular degeneration. Genetic studies revealed that STGD3 is caused by mutations in the ELOngation of ...

ELOVL4: Very long-chain fatty acids serve an eclectic role in mammalian health and function.

ELOngation of Very Long chain fatty acids-4 (ELOVL4) is an elongase responsible for the biosynthesis of very long chain (VLC, ≥C28) saturated (VLC-SFA) and polyunsaturated (VLC-PUFA) fatty acids in brain, retina, skin, Meibomian glands, and testes. Fascinatingly, different mutations in this gene have been reported to cause vastly different phenotypes in humans. Heterozygous inheritance of seven different mutations in the coding sequence and 5’ untranslated region of ELOVL4 causes autosomal dominant Stargardt-like macular dystrophy (STGD3), while homozygous inheritance of three more mutant variants causes severe seizures with ichthyosis, hypertonia, and even death. Some recent studies have described heterozygous inheritance in yet another three mutant ELOVL4 variants, two that cause spinocerebellar ataxia-34 (SCA34) with erythrokeratodermia (EKV) and one that causes SCA34 without EKV. We identified the specific enzymatic reactions catalyzed by ELOVL4 and, using a variety of genetically engineered mouse models, have actively searched for the mechanisms by which ELOVL4 impacts neural function and health. In this review, we critically compare and contrast the various animal model and case studies involving ELOVL4 deficiency via either mutation or deletion, and the resulting consequences on neuronal health and function in both the retina and central nervous system.

Very long-chain fatty acids support synaptic structure and function in the mammalian retina

Elongation of Very Long chain fatty acids-like 4 (ELOVL4) is a fatty acid elongase responsible for the biosynthesis of very long chain (VLC; ≥ C26) fatty acids in the retina, brain, skin, Meibomian gland, and testes. Heterozygous inheritance of mutant ELOVL4 causes juvenile macular degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3). Retinal photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which have been shown by our group and others to be necessary for the survival of rod photoreceptors. Our group performed a series of studies using mice conditionally depleted of retinal Elovl4 (KO) aimed at understanding the role of VLC-PUFAs in long-term retinal health and function, focusing on the role of these fatty acids in mediating synaptic function between the photoreceptors and the rest of the neural retina. The absence of VLC-PUFA from the retina of KO mice resulted in a marked decrease in retinal b-wave responses of the electroretinogram as well as a decrease in the amplitude of the oscillatory potentials mediated by the neural retina. Although there were no measureable differences between KO and wild type (WT) mice in either pre-synaptic rod calcium channel function or post-synaptic bipolar cell glutamate receptor responses, ultrastructural analysis revealed a marked decrease in the diameter of synaptic vesicles in rod terminals. Recent quantification suggests that this decrease in synaptic vesicle size due to the absence of VLC-PUFAs in KO mice, and the consequent decrease in glutamate content, could account for the decrease in b-wave response amplitudes that were previously measured in these animals.

Examination of VLC-PUFA-deficient photoreceptor terminals.

Juvenile-onset autosomal dominant Stargardt-like macular dystrophy (STGD3) is caused by mutations in ELOVL4 (elongation of very long fatty acids-4), an elongase necessary for the biosynthesis of very long chain fatty acids (VLC-FAs ≥ C26). Photoreceptors are enriched with VLC polyunsaturated fatty acids (VLC-PUFAs), which are necessary for long-term survival of rod photoreceptors. The purpose of these studies was to determine the effect of deletion of VLC-PUFAs on rod synaptic function in retinas of mice conditionally depleted (KO) of Elovl4. Retina function was assessed in wild-type (WT) and KO by electroretinography. Outer plexiform structure was evaluated by immunofluorescence and transmission electron microscopy. Single-cell recordings measured rod ion channel operation and rod bipolar glutamate signaling. Sucrose gradient centrifugation was used to isolate synaptosomes from bovine retina. Proteins and lipids were analyzed by Western blotting and tandem mass spectroscopy, respectively. Inner retinal responses (b-wave, oscillatory potentials, and scotopic threshold responses) of the ERG were decreased in the KO mice compared to controls. However the rod ion channel operation and bipolar glutamate responses were comparable between groups. Biochemical analysis revealed that conventional and ribbon synapses have VLC-PUFAs. Ultrastructural analysis showed that the outer plexiform layer was disorganized and the diameter of vesicles in rod terminals was smaller in the KO mice. Very long chain PUFAs affect rod function by contributing to synaptic vesicle size, which may alter the dynamics of synaptic transmission, ultimately resulting in a loss of neuronal connectivity and death of rod photoreceptors.

Effect of reduced retinal VLC-PUFA on rod and cone photoreceptors.

Autosomal dominant Stargardt-like macular dystrophy (STGD3) is a juvenile-onset disease that is caused by mutations in Elovl4 (elongation of very long fatty acids-4). The Elovl4 catalyzes the first step in the conversion of C24 and longer fatty acids (FAs) to very long-chain FAs (VLC-FAs, ≥C26). Photoreceptors are particularly rich in VLC polyunsaturated FAs (VLC-PUFA). To explore the role of VLC-PUFAs in photoreceptors, we conditionally deleted Elovl4 in the mouse retina. Proteins were analyzed by Western blotting and lipids by gas chromatography (GC)-mass spectrometry, GC-flame ionization detection, and tandem mass spectrometry. Retina function was assessed by electroretinography (ERG), and structure was evaluated by bright field, immunofluorescence, and transmission electron microscopy. Conditional deletion (KO) of retinal Elovl4 reduced RNA and protein levels by 91% and 96%, respectively. Total retina VLC-PUFAs were reduced by 88% compared to the wild type (WT) levels. Retinal VLC-PUFAs incorporated in phosphatidylcholine were less abundant at 12 months compared to 8-week-old levels. Amplitudes of the ERG a-wave were reduced by 22%, consistent with photoreceptor degeneration (11% loss of photoreceptors). Analysis of the rod a-wave responses gave no evidence of a role for VLC-PUFA in visual transduction. However, there were significant reductions in rod b-wave amplitudes (>30%) that could not be explained by loss of rod photoreceptors. There was no effect of VLC-PUFA reduction on cone ERG responses, and cone density was not different between the WT and KO mice at 12 months of age. The VLC-PUFAs are important for rod, but not cone, function and for rod photoreceptor longevity.

Endoplasmic reticulum microenvironment and conserved histidines govern ELOVL4 fatty acid elongase activity

Autosomal dominant Stargardt-like macular dystrophy (STGD3) in humans results from mutations in elongation of very long chain FAs-like 4 (ELOVL4), which leads to vision loss in young adults. ELOVL4 is an integral endoplasmic reticulum (ER) protein that mediates the elongation of very long chain (VLC) FAs. Mutations in ELOVL4 lead to truncation and mislocalization of the translated protein from the ER, the site of FA elongation. Little is known about the enzymatic elongation of VLC-FAs by ELOVL4. We over-expressed full-length mouse ELOVL4, an N-glycosylation-deficient mutant, an ER-retention mutant, and mutants of active site histidines to parse their individual roles in VLC-FA elongation. ELOVL4 elongated appropriate precursors to the corresponding VLC-FA species ≥28 carbons. Active site histidine mutants of ELOVL4 did not elongate appropriate precursors, establishing ELOVL4 as the elongase. Displacing ELOVL4 from the ER was sufficient to cause loss of condensation activity, while absence of N-glycosylation was irrelevant for enzyme function. This study shows that ELOVL4 enzymatic activity is governed by individual histidines in its active site and the ER microenvironment, both of which are essential for elongation of VLC-FAs.

Deciphering mutant ELOVL4 activity in autosomal-dominant Stargardt macular dystrophy

Autosomal-dominant Stargardt-like macular dystrophy [Stargardt3 (STGD3)] results from single allelic mutations in the elongation of very-long-chain fatty acids-like 4 (ELOVL4), whereas recessive mutations lead to skin and brain dysfunction. ELOVL4 protein localizes to the endoplasmic reticulum, where it mediates the condensation reaction catalyzing the formation of very-long-chain (VLC) (C-28 to C-40) fatty acids, saturated and polyunsaturated (PUFA). The defective gene product is truncated at the C terminus, leading to mislocalization and aggregation in other organelles. We hypothesized that the STGD3 truncated mutant may generate mislocalized, and therefore toxic, keto intermediates of fatty acid elongation, thereby contributing to the disease process. Using cell-based and cell-free microsome assays, we found that the truncated protein lacked innate condensation activity. Coexpression of different forms of wild-type and mutant ELOVL4 revealed a large dominant-negative effect of mutant protein on ELOVL4 localization and enzymatic activity, resulting in reduced VLC-PUFA synthesis. The reduction in VLC-PUFA levels in STGD3 and age-related macular degeneration may be a contributing factor to their retinal pathology.

ELOVL4 protein preferentially elongates 20:5n3 to very long chain PUFAs over 20:4n6 and 22:6n3

We hypothesized that reduction/loss of very long chain PUFAs (VLC-PUFAs) due to mutations in the ELOngase of very long chain fatty acid-4 (ELOVL4) protein contributes to retinal degeneration in autosomal dominant Stargardt-like macular dystrophy (STGD3) and age-related macular degeneration; hence, increasing VLC-PUFA in the retina of these patients could provide some therapeutic benefits. Thus, we tested the efficiency of elongation of C20-C22 PUFA by the ELOVL4 protein to determine which substrates are the best precursors for biosynthesis of VLC-PUFA. The ELOVL4 protein was expressed in pheochromocytoma cells, while green fluorescent protein-expressing and nontransduced cells served as controls. The cells were treated with 20:5n3, 22:6n3, and 20:4n6, either individually or in equal combinations. Both transduced and control cells internalized and elongated the supplemented FAs to C22-C26 precursors. Only ELOVL4-expressing cells synthesized C28-C38 VLC-PUFA from these precursors. In general, 20:5n3 was more efficiently elongated to VLC-PUFA in the ELOVL4-expressing cells, regardless of whether it was in combination with 22:6n3 or with 20:4n6. In each FA treatment group, C34 and C36 VLC-PUFAs were the predominant VLC-PUFAs in the ELOVL4-expressing cells. In summary, 20:5n3, followed by 20:4n6, seems to be the best precursor for boosting the synthesis of VLC-PUFA by ELOVL4 protein.

Retinal very long-chain PUFAs: new insights from studies on ELOVL4 protein

Compared with other mammalian tissues, retina is highly enriched in PUFA. Long-chain PUFA (LC-PUFA; C18-C24) are essential FAs that are enriched in the retina and are necessary for maintenance of normal retinal development and function. The retina, brain, and sperm also contain very LC-PUFA (VLC-PUFA; >C24). Although VLC-PUFA were discovered more than two decades ago, very little is known about their biosynthesis and functional roles in the retina. This is due mainly to intrinsic difficulties associated with working on these unusually long polyunsaturated hydrocarbon chains and their existence in small amounts. Recent studies on the FA elongase elongation of very long chain fatty acids-4 (ELOVL4) protein, however, suggest that VLC-PUFA probably play some uniquely important roles in the retina as well as the other tissues. Mutations in the ELOVL4 gene are found in patients with autosomal dominant Stargardt disease. Here, we review the recent literature on VLC-PUFA with special emphasis on the elongases responsible for their synthesis. We focus on a novel elongase, ELOVL4, involved in the synthesis of VLC-PUFA, and the importance of these FAs in maintaining the structural and functional integrity of retinal photoreceptors.

A Novel Mutation in theELOVL4Gene Causes Autosomal Dominant Stargardt-like Macular Dystrophy

To conduct clinical and genetic studies in a European family with autosomal dominant Stargardt-like macular dystrophy (adSTGD-like MD) and to investigate the functional consequences of a novel ELOVL4 mutation. Ophthalmic examination and mutation screening by direct sequencing of the ELOVL4 gene was performed in two affected individuals. Wild-type and mutant ELOVL4 genes were expressed as enhanced green fluorescent protein (EGFP) fusion proteins in transient transfection in NIH-3T3 and HEK293 cells. To determine the subcellular localization of ELOVL4, an endoplasmic-reticulum (ER)-specific marker for pDsRed2-ER was cotransfected with ELOVL4 constructs. Transfected cells were viewed by confocal microscopy. Western blot analysis was performed to assess protein expression using an anti-GFP antibody. Affected patients exhibited macular atrophy with surrounding flecks characteristic of adSTGD-like MD. A novel ELOVL4 p.Tyr270X mutation was detected in affected individuals. In cell-transfection studies, wild-type ELOVL4 localized preferentially to the ER. In contrast, the mutant protein appeared to be mislocalized within transfected cells. In a European family with adSTGD-like MD, a novel ELOVL4 mutation was found to underlie the disorder. Transfection studies indicated that, unlike wild-type ELOVL4, the mutant protein does not localize to the ER but rather appears to be sequestered elsewhere in an aggregated pattern in the cytoplasm. Further analysis of the function of normal and mutant ELOVL4 will provide insight into the mechanism of macular degeneration.

Autosomal dominant stargardt-like macular dystrophy: identification of a new family with a mutation in the ELOVL4 gene

Purpose To describe the clinical features and identify the mutation responsible for an autosomal dominant macular degeneration occurring in a four-generation family. Methods Family members underwent clinical examination and genealogical characterization. Mutation screening of the ELOVL4 gene was performed. Results Patients reported visual loss occurring at a mean age of 20 years. Fundus examination revealed varying degrees of central macular atrophy with or without flecks in all affected individuals. DNA sequence analysis showed a 5-bp deletion in exon 6 of the ELOVL4 gene, confirming the diagnosis of autosomal dominant Stargardt-like macular dystrophy. Genealogical analysis showed that this family represents a new affected branch of a previously described 12-generation family (31 branches) with this disorder. Conclusions We characterized a new branch of a family with autosomal dominant Stargardt-like macular dystrophy. Identification of the disease-causing gene allows for improved genetic counseling of affected individuals.

Autosomal dominant Stargardt-like macular dystrophy: founder effect and reassessment of genetic heterogeneity.

To characterize a disease-associated haplotype in 7 families with autosomal dominant Stargardt-like macular dystrophy and to determine whether these families share a common ancestor. Twenty-five polymorphic DNA markers spanning known dominant Stargardt-like gene loci were used to determine the haplotype associated with disease. In addition, an extensive genealogical investigation searching for a common ancestor shared by all of the 7 families was performed. We clinically evaluated 171 patients and genotyped 145 samples. The same DNA haplotype on chromosome 6q16 was shared by all evaluated affected members within the 7 families. In addition, we were able to genealogically join all of the families into one larger family consisting of 31 branches and 2314 individuals. Twenty-seven branches have known living descendants, with 7 branches having affected family members. In addition, we refined the critical region for the gene to approximately 1000 kilobases (kb) and eliminated part or all of 9 candidate disease-causing genes. Our study indicates that most reported cases of autosomal dominant Stargardt-like macular dystrophy in North America are part of a single larger family associated with a gene locus on chromosome 6q16. Furthermore, the DNA haplotype associated with disease is useful in excluding individuals with phenotypically similar retinal conditions. The disease-associated haplotype allows for more accurate genetic counseling to be given to individuals with a Stargardt-like phenotype inherited in an autosomal dominant pattern.

Autosomal dominant Stargardt-like macular dystrophy: I. Clinical characterization, longitudinal follow-up, and evidence for a common ancestry in families linked to chromosome 6q14

Purpose: Characterize the phenotype of autosomal dominant Stargardt-like macular dystrophy in two families linked to chromosome 6q14 and determine whether they share a common ancestry. Methods: Two families spanning 10 generations were identified and studied independently. Participating members were examined and genetic linkage and genotyping performed. Results: Presenting symptoms included decreased vision, hemeralopia, and mild photophobia. The subjective onset of visual loss ranged from age 3 to 50 with a mean of 14 years. A Snellen acuity of 20/200 occurred at a mean age of 22 years. Over decades, the macular lesion enlarged and visual acuity decreased to 20/300 to 20/800. The typical phenotype was well-circumscribed, homogenous atrophy of the retinal pigment epithelium and choriocapillaris in the macula, with surrounding yellow flecks and temporal optic nerve pallor. The phenotypic spectrum included a pattern dystrophy-like appearance, diffuse geographic atrophy, and extensive fundus flecks. Genotyping revealed that the two families were linked to chromosome 6q14 and shared a common haplotype spanning 21 cM between D6S430 and D6S300. The two families were subsequently shown by genealogic investigation to represent different branches of a common kindred. Conclusions: Families with autosomal dominant Stargardt-like macular dystrophy linked to chromosome 6q14 share a common phenotype and in some cases can be distinguished from similar dystrophies by inheritance pattern and clinical features. The finding that these two families shared a common ancestor suggests the existence of a founder effect. Characterization of the gene for autosomal dominant Stargardt-like macular dystrophy may enable better understanding of this condition and elucidation of its potential role in other forms of macular degeneration.

Assessment of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene localised to 6q13-q15 in autosomal dominant Stargardt-like disease (ADSTGD), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1).

We have recently characterised the genomic organisation of a novel interphotoreceptor matrix proteoglycan, IMPG1, and have mapped the gene locus to chromosome 6q13-q15 by fluorescence in situ hybridisation. As the...

Genomic organization and chromosomal localization of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene: a candidate for 6q-linked retinopathies

The interphotoreceptor matrix is a unique extracellular matrix occupying the space between the photoreceptors and the retinal pigment epithelium. Due to its putative function in the maintenance and integrity of the photoreceptor cells, it is conceivable that it is involved in retinal degeneration processes. More recently, a novel gene encoding a 150-kDa interphotoreceptor matrix proteoglycan, designated IMPG1, was cloned and shown to be expressed in both rod and cone photoreceptor cells. To assess this gene in human retinal dystrophies, we have now determined the genomic organization and chro- mosome location of IMPG1. It is composed of 17 exons ranging from 21 to 533 bp, including an alternatively spliced exon 2. Using somatic cell hybrid mapping and FISH analysis, we have assigned the IMPG1 locus to 6q13→q15. As this interval overlaps with the chromosomal loci of several human retinopathies, including autosomal dominant Stargardt-like macular dystrophy (STGD3), progressive bifocal chorioretinal atrophy (PBCRA), and North Carolina macular dystrophy (MCDR1), IMPG1 represents an attractive candidate for these 6q-linked disorders.