Alternative titles; symbols
HGNC Approved Gene Symbol: IMPG1
Cytogenetic location: 6q14.1 Genomic coordinates (GRCh38): 6:75,921,114-76,072,662 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q14.1 | Macular dystrophy, vitelliform, 4 | 616151 | Autosomal dominant; Autosomal recessive | 3 |
| Retinitis pigmentosa 91 | 153870 | Autosomal dominant | 3 |
Interphotoreceptor matrix glycoconjugates, which are largely proteoglycans, appear to participate in retinal adhesion and in maintaining photoreceptor viability. Kuehn and Hageman (1995) isolated monkey interphotoreceptor matrix proteoglycan-1 (Impg1), which the authors designated IPM-150, from an SDS-polyacrylamide gel and utilized amino acid sequence data from the isolated protein to design RT-PCR primers for amplification of monkey retinal mRNA. They used the resulting clone to screen a human cDNA library and isolated an 809-bp cDNA, which shares 97% homology with the monkey sequence and encodes human IMPG1. The putative protein, a chondroitin 6-sulfate proteoglycan, contains 4 consensus sequences for hyaluronan binding and 3 for N-glycosylation, as well as several potential O-glycosylation sites.
Felbor et al. (1998) determined that the IMPG1 gene contains 17 exons, including an alternatively spliced exon 2.
Using somatic cell hybrid mapping and fluorescence in situ hybridization analysis, Felbor et al. (1998) mapped the IMPG1 gene to chromosome 6q13-q15.
Gross (2015) mapped the IMPG1 gene to chromosome 6q14.1 based on an alignment of the IMPG1 sequence (GenBank AF017776) with the genomic sequence (GRCh38).
Ishikawa et al. (2015) reviewed the structure of the highly organized interphotoreceptor matrix (IPM) and its interconnected domains surrounding cone and rod photoreceptors and its extension throughout the photoretinal space. They discussed the function of genes within the IPM and their role in retinal degenerative disorders.
Vitelliform Macular Dystrophy 4
In affected members of 1 Spanish and 2 French families segregating autosomal dominant vitelliform macular dystrophy (VMD4; 616151), Manes et al. (2013) identified heterozygosity for a missense mutation in the IMPG1 gene (L238R; 602870.0001). Sequencing of IMPG1 in additional VMD patients identified a French family in which an affected brother and sister were compound heterozygous for a nonsense (R507X; 602870.0002) and a missense (L154P; 602870.0003) mutation, and a consanguineous Italian family in which an affected brother and sister were homozygous for a splice site mutation (602870.0004). Asymptomatic heterozygous carriers from both of the latter families were found to exhibit minor fundus changes. Screening of the IMPG1 gene in patients with other forms of inherited macular dystrophy or macular drusen failed to reveal any mutations. Because none of the patients with benign concentric annular macular dystrophy (BCAMD; 153870) reported by van Lith-Verhoeven et al. (2004) (see below) showed vitelliform deposits, and because in the 6 VMD families no individuals exhibited any annular atrophy in the macular area and aged individuals did not show signs of retinitis pigmentosa, Manes et al. (2013) concluded that the VMD4 phenotype is distinct from that of BCAMD.
In a 25-year-old woman with VMD, Gupta et al. (2021) identified heterozygosity for the previously reported L154P mutation in the IMPG1 gene. Her father, who had been diagnosed with central serous chorioretinopathy, was also heterozygous for the variant; he did not show findings of VMD, suggesting incomplete penetrance. The authors also noted that it was possible that a second IMPG1 mutation was present in the deep intronic or promoter regions that were not sequenced in the proband.
In a cohort of 106 unrelated patients with VMD who were negative for mutation in the BEST1 (607854) and PRPH2 (179605) genes, Brandl et al. (2017) screened the IMPG1 and IMPG2 (607056) genes and identified a Turkish boy who was homozygous for a splicing mutation in IMPG1 (602870.0005). The authors also identified patients with mutations in IMPG2 (see VMD5, 616152) and noted remarkable similarity in the clinical appearance of IMPG1 and IMPG2 mutation carriers, although symptoms tended to be more severe in those with IMPG1 mutations.
By gene-panel testing and exome sequencing in 596 families with RP and VMD, Olivier et al. (2021) identified IMPG1 mutations in 11 families, including 2 with VMD and 1 in which both VMD and retinitis pigmentosa were diagnosed (see, e.g., 602870.0007-602870.0008).
Retinitis Pigmentosa 91
In affected members of a 4-generation Dutch family with retinitis pigmentosa (RP91; 153870) mapping to chromosome 6p12.3-q16, originally reported by Deutman (1974) and diagnosed with benign concentric annular macular dystrophy, van Lith-Verhoeven et al. (2004) screened 5 candidate genes and identified heterozygosity for a missense mutation in the IMPG1 gene (L579P; 602870.0006). The mutation segregated fully with disease in the family and was not found in 190 control individuals. The authors noted that the mutation was not predicted to have a major effect on the protein, and stated that study of additional patients was necessary to establish the causality of the mutation.
By gene-panel testing and exome sequencing in 596 families with RP and VMD, Olivier et al. (2021) identified IMPG1 mutations in 11 families, including 6 with RP (see, e.g., 602870.0007 and 602870.0009).
Exclusion Studies
Gehrig et al. (1998) found no disease-associated mutations in the IMPG1 gene in an affected member of a family with autosomal dominant Stargardt-like macular dystrophy (STGD3; 600110) or in patients from 6q-linked multigenerational families diagnosed with progressive bifocal chorioretinal atrophy (600790) or North Carolina macular dystrophy (136550).
Olivier et al. (2021) generated medaka fish with knockdown of Impg1 or Impg2 (607056). Both sets of morphant retinas displayed significant alteration in photoreceptor morphology, with an approximately 20% reduction in length of the outer segments of rod photoreceptors, and a 90% reduction in outer segment length of cone photoreceptors, compared to control fish. The authors concluded that both Impg1 and Impg2 are necessary for proper photoreceptor morphology.
In affected members from 3 multiplex families with autosomal dominant vitelliform macular dystrophy (VMD4; 616151), 2 French and 1 Spanish, Manes et al. (2013) identified heterozygosity for a c.713T-G transversion in exon 7 of the IMPG1 gene, resulting in a leu238-to-pro (L238P) substitution at a conserved residue in the start of the N-terminal SEA1 domain. The mutation segregated with disease in all 3 families and was not found in public SNP databases or in 114 ethnically matched controls. Haplotype analysis demonstrated that all affected individuals shared the same alleles of the 2 markers flanking IMPG1, D6S456 and D6S1589, indicating that the 3 families might be distantly related.
In a French brother and sister with vitelliform macular dystrophy (VMD4; 616151), Manes et al. (2013) identified compound heterozygosity for a c.1519C-T transition in exon 13 of the IMPG1 gene, resulting in an arg507-to-ter (R507X) substitution, and a c.461T-C transition in exon 3, resulting in a leu154-to-pro (L154P; 602870.0003) substitution at a conserved residue. The L154P mutation was not found in public SNP databases, and the R507X mutation was found at low frequency (1/13,006 alleles) in the Exome Variant Server database. The sibs' asymptomatic father carried the nonsense mutation; DNA was unavailable from their deceased mother. In addition, 4 asymptomatic children were heterozygous for 1 of the mutations: on examination, the sister's son, who carried the L154P missense mutation, had a slight defect in the line between the inner and outer segments in the nasal parafovea of the left eye, whereas her daughter, who carried the R507X nonsense mutation, had normal funduscopy.
For discussion of the leu154-to-pro (L154P) mutation in the IMPG1 gene that was found in compound heterozygous state in patients with vitelliform macular dystrophy (VMD4; 616151) by Manes et al. (2013), see 602870.0002.
In a 25-year-old woman with VMD, Gupta et al. (2021) identified heterozygosity for the previously reported L154P mutation (c.461C-T) in the IMPG1 gene. She also carried a splicing and a missense variant of unknown significance in the ABCA4 gene (601691). Her father, who had been diagnosed with central serous chorioretinopathy, was also heterozygous for the IMPG1 variant; he did not show findings of VMD, suggesting incomplete penetrance. The authors stated that the 1000 Genomes Project, EVS, and gnomAD databases showed the variant to have a minor allele frequency of 0.00004118 overall and of 0.00008071 in the European non-Finnish population. The authors noted that it was possible that a second IMPG1 mutation was present in the deep intronic or promoter regions that were not sequenced.
In a brother and sister from a consanguineous Italian family with vitelliform macular dystrophy (VMD4; 616151), Manes et al. (2013) identified homozygosity for a c.807+1G-T transversion in intron 7 of the IMPG1 gene. The mutation was not found in public SNP databases. The homozygous sibs exhibited macular as well as additional multifocal vitelliform deposits. Fundus examination of their asymptomatic parents, who were heterozygous for the mutation, revealed tiny extramacular vitelliform deposits in both.
In a Turkish boy (family 11-151) with vitelliform macular dystrophy (VMD4; 616151), Brandl et al. (2017) identified homozygosity for a splicing mutation (c.807+5G-A) in intron 7 of the IMPG1 gene, predicted to weaken the donor splice site by 20%. Analysis of transfected HEK293 cells revealed aberrant pre-mRNA splicing, with skipping of exon 7 in approximately half of transcripts resulting in a 194-bp product as well as the 335-bp product found in controls. In addition, a faint 270-bp band of unknown origin was observed in cells transfected with the mutant construct. The proband's unaffected parents, who had full visual acuity and unremarkable findings on multimodal retinal imaging, were heterozygous for the mutation.
In affected members of a large 4-generation Dutch family with retinitis pigmentosa showing early macular involvement (RP91; 153870), originally reported by Deutman (1974) and diagnosed with benign concentric macular dystrophy, van Lith-Verhoeven et al. (2004) identified heterozygosity for a c.1866T-C transition in exon 13 of the IMPG1 gene, resulting in a leu579-to-pro (L579P) substitution. The mutation segregated fully with disease in the family and was not found in 190 controls.
Olivier et al. (2021) reexamined 10 affected family members (family L) of the Dutch family originally reported by Deutman (1974) and revised the diagnosis to RP with relatively early macular involvement. Olivier et al. (2021) noted that the mutation was a c.1736T-C transition (c.1736T-C, NM_001563) in IMPG1 and that the L579P variant was not present in the gnomAD database.
Retinitis Pigmentosa 91
In affected members of a large 4-generation French family (family A) and a 49-year-old Spanish woman (family C) with retinitis pigmentosa (RP91; 153870), Olivier et al. (2021) identified heterozygosity for a splicing mutation (c.1824+1G-A, NM_001563) in intron 13 of the IMPG1 gene. The mutation segregated fully with disease in the French family, being present in 6 affected individuals who had RP ranging in severity from mild to severe, as well as in 4 asymptomatic carriers in the youngest generation designated as 'preclinical,' who had grossly normal fundus examinations but showed abnormalities on imaging studies. The variant was also detected in the Spanish proband's asymptomatic 70-year-old mother, who had hard drusen-like deposits in the macula on funduscopy but did not undergo other ocular imaging. The variant was reported at low minor allele frequency in the gnomAD database (1/241,072).
Vitelliform Macular Dystrophy 4
In a 47-year-old French woman (family B) with vitelliform macular dystrophy (VMD4; 616151), Olivier et al. (2021) identified heterozygosity for the c.1824+1G-A splicing mutation in the IMPG1 gene. The proband had reduced visual acuity with the typical vitelliform lesions seen on funduscopy; ocular coherence tomography revealed a hyperreflective deposit on the right and inactive choroidal neovascularization on the left, and electroretinography showed preserved rod and cone responses with a normal Arden ratio on electrooculogram. Her 2 sisters, aged 45 and 50 years, were asymptomatic carriers of the variant and had normal funduscopic examinations; other ocular studies were not reported. Their 70-year-old mother with 'low vision' also carried the variant; no other clinical details were available.
In 2 affected mother/daughter pairs from unrelated British families (families F and G) with vitelliform macular dystrophy (VMD4; 616151), Olivier et al. (2021) identified heterozygosity for a c.960T-A transversion (c.960T-A, NM_001563) in the IMPG1 gene, resulting in a ser320-to-arg (S320R) substitution. The variant was not present in the gnomAD database. Funduscopy in the asymptomatic 58-year-old mother in family F revealed bone-spicule pigmentation in the inferior sector of the retina, and ocular coherence tomography showed thinning of the outer retinal layers in the periphery; she was diagnosed with retinitis pigmentosa.
In a 3-generation French family (family E) with retinitis pigmentosa (RP91; 153870), Olivier et al. (2021) identified heterozygosity for a c.1838T-C transition (c.1838T-C, NM_001563) in the IMPG1 gene, resulting in a leu613-to-pro (L613P) substitution. The variant was not present in the gnomAD database. The 68-year-old proband's 72-year-old affected sister also carried the variant, as did his asymptomatic 40-year-old son, who had a normal funduscopic examination but showed a slightly less visible ellipsoid zone in the macular periphery on ocular coherence tomography; other ocular tests were not reported.
Brandl, C., Schulz, H. L., Issa, P. C., Birtel, J., Bergholz, R., Lange, C., Dahlke, C., Zobor, D., Weber, B. H. F., Stohr, H. Mutations in the genes for interphotoreceptor matrix proteoglycans, IMPG1 and IMPG2, in patients with vitelliform macular lesions. Genes (Basel) 8: 170, 2017. [PubMed: 28644393] [Full Text: https://doi.org/10.3390/genes8070170]
Deutman, A. F. Benign concentric annular macular dystrophy. Am. J. Ophthal. 78: 384-396, 1974. [PubMed: 4412179] [Full Text: https://doi.org/10.1016/0002-9394(74)90225-6]
Felbor, U., Gehrig, A., Sauer, C. G., Marquardt, A., Kohler, M., Schmid, M., Weber, B. H. F. Genomic organization and chromosomal localization of the interphotoreceptor matrix proteoglycan-1 (IMPG1) gene: a candidate for 6q-linked retinopathies. Cytogenet. Cell Genet. 81: 12-17, 1998. [PubMed: 9691169] [Full Text: https://doi.org/10.1159/000015001]
Gehrig, A., Felbor, U., Kelsell, R. E., Hunt, D. M., Maumenee, I. H., Weber, B. H. F. 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). J. Med. Genet. 35: 641-645, 1998. [PubMed: 9719369] [Full Text: https://doi.org/10.1136/jmg.35.8.641]
Gross, M. B. Personal Communication. Baltimore, Md. 1/13/2015.
Gupta, M. P., Brodie, S. E., Freund, K. B. Unusual early-onset vitelliform dystrophy possible linked to the interphotoreceptor matrix proteoglycan-1 p.leu154pro mutation. Retin. Cases Brief Rep. 15: 527-531, 2021. [PubMed: 30688845] [Full Text: https://doi.org/10.1097/ICB.0000000000000843]
Ishikawa, M., Sawada, Y., Yoshitomi, T. Structure and function of the interphotoreceptor matrix surrounding retinal photoreceptor cells. Exp. Eye Res. 133: 3-18, 2015. [PubMed: 25819450] [Full Text: https://doi.org/10.1016/j.exer.2015.02.017]
Kuehn, M. H., Hageman, G. S. Characterization of a cDNA encoding IPM 150, a novel human interphotoreceptor matrix chondroitin 6-sulfate proteoglycan. (Abstract) Invest. Ophthal. Vis. Sci. 36: 510 only, 1995.
Manes, G., Meunier, I., Avila-Fernandez, A., Banfi, S., Le Meur, G., Zanlonghi, X., Corton, M., Simonelli, F., Brabet, P., Labesse, G., Audo, I., Mohand-Said, S., and 16 others. Mutations in IMPG1 cause vitelliform macular dystrophies. Am. J. Hum. Genet. 93: 571-578, 2013. [PubMed: 23993198] [Full Text: https://doi.org/10.1016/j.ajhg.2013.07.018]
Olivier, G., Corton, M., Intartaglia, D., Verbakel, S. K., Sergouniotis, P. I., Le Meur, G., Dhaenens, C.-M., Naacke, H., Avila-Fernandez, A., Hoyng, C. B., Klevering, J., Bocquet, B., and 12 others. Pathogenic variants in IMPG1 cause autosomal dominant and autosomal recessive retinitis pigmentosa. J. Med. Genet. 58: 570-578, 2021. [PubMed: 32817297] [Full Text: https://doi.org/10.1136/jmedgenet-2020-107150]
van Lith-Verhoeven, J. J. C., Hoyng, C. B., van den Helm, B., Deutman, A. F., Brink, H. M. A., Kemperman, M. H., de Jong, W. H. M., Kremer, H., Cremers, F. P. M. The benign concentric annular macular dystrophy locus maps to 6p12.3-q16. Invest. Ophthal. Vis. Sci. 45: 30-35, 2004. [PubMed: 14691150] [Full Text: https://doi.org/10.1167/iovs.03-0392]