Developmental Basis of Nanophthalmos: MFRP Is Required for both Prenatal Ocular Growth and Postnatal Emmetropization

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

“…Complex cases with retinal involvement (RP features or ERG changes) were found in 6/19 (31.6%) of the families with a molecular diagnosis, mostly due to MFRP mutations (5/6, 83.3%). The retinal involvement in the MFRP-associated group is in line with previous phenotypic studies 39 and is in agreement with its expression pattern in human, mouse and zebrafish eyes www.nature.com/scientificreports www.nature.com/scientificreports/ including neural and pigmentary retina 3,20,21 and its role in photoreceptor outer segment maintenance 50 . An additional explanation could be the fact that MFRP and a gene implicated in late-onset retinal dystrophy, C1QTNF5 (encoding C1q and tumor necrosis factor related protein 5) are both expressed as a bicistronic transcript and found to co-localize to the same tissues with a clear functional relationship in the retina 51,52 .…”

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

“…Complex cases with retinal involvement (RP features or ERG changes) were found in 6/19 (31.6%) of the families with a molecular diagnosis, mostly due to MFRP mutations (5/6, 83.3%). The retinal involvement in the MFRP-associated group is in line with previous phenotypic studies 39 and is in agreement with its expression pattern in human, mouse and zebrafish eyes www.nature.com/scientificreports www.nature.com/scientificreports/ including neural and pigmentary retina 3,20,21 and its role in photoreceptor outer segment maintenance 50 . An additional explanation could be the fact that MFRP and a gene implicated in late-onset retinal dystrophy, C1QTNF5 (encoding C1q and tumor necrosis factor related protein 5) are both expressed as a bicistronic transcript and found to co-localize to the same tissues with a clear functional relationship in the retina 51,52 .…”

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error

“…Thus, the impact of PRSS56 mutations on human ocular growth is likely to begin prenatally before patterned visual activity modulates the rate of ocular growth. These findings are in agreement with previous suggestions that genetic alterations leading to nanophthalmos interfere with prenatal ocular growth [ 14 ]. Importantly, ablation of Prss56 following eye opening in the mouse (tamoxifen injection at P13 and P18) resulted in a modest reduction in ocular dimension and a hyperopic shift in refraction ( Fig 7E, 7J and 7M ), suggesting that the role of PRSS56 in ocular growth regulation may extend beyond the prenatal developmental window in humans.…”

Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects

“…8,23,24 Like other dicistronic genes, MFRP and CTRP5 may participate in a common biological pathway in RPE, but no functional relationship between MFRP and CTRP5 has been proposed. Several studies have confirmed that CTRP5 is a binding partner of MFRP, 7,9,10,12 but here, we provided evidence for an inverse relationship between these two binding partners. Expression of MFRP in iPS-RPE derived from our two MFRP-mutant patients is lower compared to wild-type controls.…”

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

“…Complex cases with retinal involvement (RP features or ERG changes) were found in 6/19 (31.6%) of the families with a molecular diagnosis, mostly due to MFRP mutations (5/6, 83.3%). The retinal involvement in the MFRP-associated group is in line with previous phenotypic studies 39 and is in agreement with its expression pattern in human, mouse and zebrafish eyes www.nature.com/scientificreports www.nature.com/scientificreports/ including neural and pigmentary retina 3,20,21 and its role in photoreceptor outer segment maintenance 50 . An additional explanation could be the fact that MFRP and a gene implicated in late-onset retinal dystrophy, C1QTNF5 (encoding C1q and tumor necrosis factor related protein 5) are both expressed as a bicistronic transcript and found to co-localize to the same tissues with a clear functional relationship in the retina 51,52 .…”

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error

“…Thus, the impact of PRSS56 mutations on human ocular growth is likely to begin prenatally before patterned visual activity modulates the rate of ocular growth. These findings are in agreement with previous suggestions that genetic alterations leading to nanophthalmos interfere with prenatal ocular growth [ 14 ]. Importantly, ablation of Prss56 following eye opening in the mouse (tamoxifen injection at P13 and P18) resulted in a modest reduction in ocular dimension and a hyperopic shift in refraction ( Fig 7E, 7J and 7M ), suggesting that the role of PRSS56 in ocular growth regulation may extend beyond the prenatal developmental window in humans.…”

Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects

“…8,23,24 Like other dicistronic genes, MFRP and CTRP5 may participate in a common biological pathway in RPE, but no functional relationship between MFRP and CTRP5 has been proposed. Several studies have confirmed that CTRP5 is a binding partner of MFRP, 7,9,10,12 but here, we provided evidence for an inverse relationship between these two binding partners. Expression of MFRP in iPS-RPE derived from our two MFRP-mutant patients is lower compared to wild-type controls.…”

The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56

“…Complex cases with retinal involvement (RP features or ERG changes) were found in 6/19 (31.6%) of the families with a molecular diagnosis, mostly due to MFRP mutations (5/6, 83.3%). The retinal involvement in the MFRP-associated group is in line with previous phenotypic studies 39 and is in agreement with its expression pattern in human, mouse and zebrafish eyes www.nature.com/scientificreports www.nature.com/scientificreports/ including neural and pigmentary retina 3,20,21 and its role in photoreceptor outer segment maintenance 50 . An additional explanation could be the fact that MFRP and a gene implicated in late-onset retinal dystrophy, C1QTNF5 (encoding C1q and tumor necrosis factor related protein 5) are both expressed as a bicistronic transcript and found to co-localize to the same tissues with a clear functional relationship in the retina 51,52 .…”

Müller glia-derived PRSS56 is required to sustain ocular axial growth and prevent refractive error

“…Thus, the impact of PRSS56 mutations on human ocular growth is likely to begin prenatally before patterned visual activity modulates the rate of ocular growth. These findings are in agreement with previous suggestions that genetic alterations leading to nanophthalmos interfere with prenatal ocular growth [ 14 ]. Importantly, ablation of Prss56 following eye opening in the mouse (tamoxifen injection at P13 and P18) resulted in a modest reduction in ocular dimension and a hyperopic shift in refraction ( Fig 7E, 7J and 7M ), suggesting that the role of PRSS56 in ocular growth regulation may extend beyond the prenatal developmental window in humans.…”

Gene Therapy in Patient-specific Stem Cell Lines and a Preclinical Model of Retinitis Pigmentosa With Membrane Frizzled-related Protein Defects

“…8,23,24 Like other dicistronic genes, MFRP and CTRP5 may participate in a common biological pathway in RPE, but no functional relationship between MFRP and CTRP5 has been proposed. Several studies have confirmed that CTRP5 is a binding partner of MFRP, 7,9,10,12 but here, we provided evidence for an inverse relationship between these two binding partners. Expression of MFRP in iPS-RPE derived from our two MFRP-mutant patients is lower compared to wild-type controls.…”