Alternative titles; symbols
HGNC Approved Gene Symbol: IMPG2
Cytogenetic location: 3q12.3 Genomic coordinates (GRCh38) : 3:101,222,546-101,320,575 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3q12.3 | Macular dystrophy, vitelliform, 5 | 616152 | Autosomal dominant | 3 |
| Retinitis pigmentosa 56 | 613581 | Autosomal recessive | 3 |
Interphotoreceptor matrix proteoglycan-2 is part of an extracellular complex occupying the interface between photoreceptors and the retinal pigment epithelium in the fundus of the eye (summary by Acharya et al., 2000).
Kuehn and Hageman (1999) cloned human IMPG2, encoding a novel chondroitin sulfate proteoglycan, which they designated IPM200, from the retinal interphotoreceptor matrix. The deduced 1,241-amino acid protein has a calculated molecular mass of 138.5 kD. Northern blot analysis detected a single 6.2-kb transcript in human retina.
Acharya et al. (2000) also cloned IMPG2, which they called SPACRCAN, from a human retina cDNA library. The deduced 1,160-amino acid protein contains a large central mucin domain, 3 consensus sites for glycosaminoglycan attachment, 2 epidermal growth factor-like repeats, a putative hyaluronan-binding motif, and a potential transmembrane domain near the C terminus. By Northern blot analysis, Acharya et al. (2000) detected a predominant, approximately 9-kb transcript and a more diffuse 4.4-kb transcript, with restricted expression in the retina and pineal gland. By in situ hybridization, they localized IMPG2 within the interphotoreceptor matrix, surrounding both rods and cones. By Northern blot analysis and RT-PCR, Kuehn et al. (2001) showed that IMPG2 is processed in the human retina into multiple alternatively sized transcripts that may represent splice variants.
Kuehn et al. (2001) determined that the IMPG2 gene contains 19 exons and spans at least 31.0 kb. Based on an analysis of the overall relationship of human IMPG2 to human IMPG1 (602870), Kuehn et al. (2001) suggested that the genes evolved from a common ancestral gene.
By radiation hybrid analysis and FISH, Kuehn and Hageman (1999) mapped the IMPG2 gene to chromosome 3q12.2-q12.3. By the same methods, Acharya et al. (2000) mapped the IMPG2 gene to chromosome 3q11.2.
Retinitis Pigmentosa 56
Bandah-Rozenfeld et al. (2010) analyzed the candidate gene IMPG2 in 12 families segregating autosomal recessive retinal disease mapping to chromosome 3q12 and identified homozygous mutations in 7 of them (see, e.g., 607056.0001-607056.0005). In 5 families with a truncating mutation and in 1 with a 1.8-kb intragenic deletion, affected individuals were diagnosed with retinitis pigmentosa (RP56; 613581), whereas the 1 patient with a missense mutation (F124L; 607056.0005) had mild maculopathy.
Vitelliform Macular Dystrophy 5
In a father and son with vitelliform macular dystrophy (VMD5; 616152), Meunier et al. (2014) identified heterozygosity for a missense mutation in the IMPG2 gene (C1077F; 607056.0006). Meunier et al. (2014) noted that homozygosity for a missense mutation in IMPG2 (F124L; 607056.0005) had previously been identified by Bandah-Rozenfeld et al. (2010) in a patient with mild maculopathy, which Meunier et al. (2014) designated as representing 'a case of autosomal recessive macular vitelliform dystrophy.'
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 genes and identified 8 probands with heterozygous mutations in IMPG2 (see, e.g., 607056.0006-607056.0007). The authors also identified patients with mutations in IMPG1 (see VMD4, 616151) 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.
Exclusion Studies
Kuehn et al. (2001) analyzed the coding regions of the IMPG2 gene in 224 probands with various retinal diseases, but found no mutations.
In 3 sisters from a consanguineous Iraqi Jewish family (family MOL0764) with retinitis pigmentosa (RP56; 613581), Bandah-Rozenfeld et al. (2010) identified homozygosity for a 635C-G transversion in exon 6 of the IMPG2 gene, resulting in a ser212-to-ter (S212X) substitution. The mutation was not detected in 47 additional RP patients of Oriental Jewish origin, primarily from Iraq, Iran, and Afghanistan, or in 98 Israeli and Palestinian RP patients of other origins; however, it was found in 1 of 104 controls of Oriental Jewish ancestry. The 3 sisters were diagnosed with RP and myopia in childhood, and in their sixth decade had advanced RP with very low visual acuity, ranging from counting fingers to light perception only, with atropic macular changes and severely constricted visual fields. Full-field electroretinogram (ERG) responses were extinguished in all 3 sibs. All 3 also had posterior subcapsular cataracts; 1 sister also had nuclear cataract.
In 3 sibs from a Dutch family (family W01-299) with retinitis pigmentosa (RP56; 613581), Bandah-Rozenfeld et al. (2010) identified homozygosity for a 1,850-bp deletion (c.888-1554_908+274del) that removes exon 9 of the IMPG2 gene, resulting in absence of 7 amino acids in a conserved SEA domain. The deletion was not found in 270 Dutch controls or in more than 700 probands of European origin with isolated or autosomal recessive RP. Transient transfection of COS-1 cells showed that a construct expressing the wildtype SEA domain was properly targeted to the plasma membrane, whereas the mutant lacking the 7 amino acids appeared to be retained in the endoplasmic reticulum. The 3 affected sibs were diagnosed with RP before 15 years of age, and visual acuity ranged from 20/32 to 20/125 at the time of presentation. ERG responses in 2 of the sibs showed a rod-cone pattern and deteriorated over time. Posterior subcapsular cataracts led to cataract extraction in all 3 patients around the age of 30 years. All 3 displayed bull's-eye maculopathy.
In 2 Dutch brothers from a consanguineous Dutch family (family W08-1378) with retinitis pigmentosa (RP56; 613581), Bandah-Rozenfeld et al. (2010) identified homozygosity for a 2716C-T transition in the IMPG2 gene, resulting in an arg906-to-ter (R906X) substitution. The mutation, which was not found in more than 100 ethnically matched controls, was also detected in heterozygosity in a sporadic RP Dutch patient in whom another mutation in the IMPG2 gene was not identified on the second allele. The brothers presented with early-onset night blindness and diminished color vision and were diagnosed with cone-rod dystrophy in their teens. At age 30, they both displayed moderate myopia, waxy pallor of the optic disc, narrow vessels, peripheral bone spicules, and an undetectable ERG response. The proband had a relatively intact macula with a visual acuity of 20/80 in both eyes and only loss of sensitivity in the central visual field. His younger brother, however, had patches of retinal pigment epithelium atrophy in the macula with visual acuity of 20/80 in the right eye but was only able to count fingers with the left eye; visual field testing revealed a central scotoma in both eyes. At ages 39 and 36 years, both brothers had mild cortical cataract.
In a 68-year-old Italian woman (family NAP1) with retinitis pigmentosa (RP56; 613581), born of second-cousin parents, Bandah-Rozenfeld et al. (2010) identified homozygosity for a 2890C-T transition in the IMPG2 gene, resulting in an arg964-to-ter (R964X) substitution. The mutation was not found in more than 100 ethnically matched controls. The patient was diagnosed with RP at age 30 years; examination at age 68 revealed advanced RP with atrophic macular changes, very low visual acuity (detection of hand motion bilaterally), exotropia of the right eye, nystagmus, posterior subcapsular cataracts, and extinguished ERG responses.
In an Israeli Christian Arab woman (family MOL0732), born of first-cousin parents, who was diagnosed with mild maculopathy (VMD5; 616152) at 63 years of age, Bandah-Rozenfeld et al. (2010) identified homozygosity for a 370T-C transition in the IMPG2 gene, resulting in a phe124-to-leu (F124L) substitution at a highly conserved residue. Full-field ERG responses were within normal limits, and color vision was normal. Optical coherence tomography revealed elevation of the photoreceptor layer in the foveal region. She had mild nuclear sclerosis, and visual field testing revealed a relative central scotoma in the right eye. Meunier et al. (2014) designated the 'mild maculopathy' in this patient as 'a case of autosomal recessive vitelliform macular dystrophy.' No heterozygous carriers were examined.
In a father and son with vitelliform macular dystrophy (VMD5; 616152), Meunier et al. (2014) identified heterozygosity for a c.3230G-T transversion in the IMPG2 gene, resulting in a cys1077-to-phe (C1077F) substitution in the second EGF-like domain. The father's affected sister was also heterozygous for the mutation, which was not found in an unaffected daughter, in 57 ophthalmologically unaffected and ethnically matched controls with no personal or family history of macular degeneration or retinal dystrophy, or in public SNP databases.
In a 70-year-old woman (family 8-553) who was diagnosed at age 64 with VMD, Brandl et al. (2017) identified heterozygosity for the C1077F mutation in the IMPG2 gene. Her 31-year-old son, who reported problems with reading, had visual acuity of 20/30 in the right eye and a dome-shaped foveal detachment with material above the retinal pigment epithelium (RPE) and defects at the photoreceptor inner/outer segment junction (ellipsoid zone) on spectral-domain optical coherence tomography (SD-OCT). His left eye had 20/20 visual acuity but SD-OCT revealed mild subfoveal accumulation of hyperreflective material without RPE or photoreceptor abnormalities.
In a 54-year-old man (family 9-399) who was diagnosed at age 47 with vitelliform macular dystrophy (VMD5; 616152), Brandl et al. (2017) identified heterozygosity for a c.727G-C transversion in exon 7 of the IMPG2 gene, resulting in an ala243-to-pro (A243P) substitution. The variant was not found in the ExAC database. His 44-year-old asymptomatic sister, who was also heterozygous for the A243P variant, was found to have slightly reduced visual acuity of 20/25 in the left eye and bilateral foveal lesions on spectral-domain optical coherence tomography, more severe on the left than the right.
Acharya, S., Foletta, V. C., Lee, J. W., Rayborn, M. E., Rodriguez, I. R., Young, W. S., III, Hollyfield, J. G. SPACRCAN, a novel human interphotoreceptor matrix hyaluronan-binding proteoglycan synthesized by photoreceptors and pinealocytes. J. Biol. Chem. 275: 6945-6955, 2000. [PubMed: 10702256] [Full Text: https://doi.org/10.1074/jbc.275.10.6945]
Bandah-Rozenfeld, D., Collin, R. W. J., Banin, E., van den Born, I., Coene, K. L. M., Siemiatkowska, A. M., Zelinger, L., Khan, M. I., Lefeber, D. J., Erdinest, I., Testa, F., Simonelli, F., and 9 others. Mutations in IMPG2, encoding interphotoreceptor matrix proteoglycan 2, cause autosomal-recessive retinitis pigmentosa. Am. J. Hum. Genet. 87: 199-208, 2010. [PubMed: 20673862] [Full Text: https://doi.org/10.1016/j.ajhg.2010.07.004]
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]
Kuehn, M. H., Hageman, G. S. Molecular characterization and genomic mapping of human IPM 200, a second member of a novel family of proteoglycans. Molec. Cell Biol. Res. Commun. 2: 103-110, 1999. [PubMed: 10542133] [Full Text: https://doi.org/10.1006/mcbr.1999.0161]
Kuehn, M. H., Stone, E. M., Hageman, G. S. Organization of the human IMPG2 gene and its evaluation as a candidate gene in age-related macular degeneration and other retinal degenerative disorders. Invest. Ophthal. Vis. Sci. 42: 3123-3129, 2001. [PubMed: 11726612]
Meunier, I., Manes, G., Bocquet, B., Marquette, V., Baudoin, C., Puech, B., Defoort-Dhellemmes, S., Audo, I., Verdet, R., Arndt, C., Zanlonghi, X., Le Meur, G., Dhaenens, C.-M., Hamel, C. P. Frequency and clinical pattern of vitelliform macular dystrophy caused by mutations of interphotoreceptor matrix IMPG1 and IMPG2 genes. Ophthalmology 121: 2406-2414, 2014. [PubMed: 25085631] [Full Text: https://doi.org/10.1016/j.ophtha.2014.06.028]