{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,13]],"date-time":"2026-10-13T20:13:02Z","timestamp":1791922382248,"version":"4.3.4"},"reference-count":44,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2022,1,30]],"date-time":"2022-01-30T00:00:00Z","timestamp":1643500800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["EY011996"],"award-info":[{"award-number":["EY011996"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"name":"The Jackson Laboratory Institutional Grant","award":["CA34196"],"award-info":[{"award-number":["CA34196"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Adipor1tm1Dgen and Mfrprd6 mutant mice share similar eye disease characteristics. Previously, studies established a functional relationship of ADIPOR1 and MFRP proteins in maintaining retinal lipidome homeostasis and visual function. However, the independent and\/or interactive contribution of both genes to similar disease phenotypes, including fundus spots, decreased axial length, and photoreceptor degeneration has yet to be examined. We performed a gene-interaction study where homozygous Adipor1tm1Dgen and Mfrprd6 mice were bred together and the resulting doubly heterozygous F1 offspring were intercrossed to produce 210 F2 progeny. Four-month-old mice from all nine genotypic combinations obtained in the F2 generation were assessed for white spots by fundus photo documentation, for axial length by caliper measurements, and for photoreceptor degeneration by histology. Two-way factorial ANOVA was performed to study individual as well as gene interaction effects on each phenotype. Here, we report the first observation of reduced axial length in Adipor1tmlDgen homozygotes. We show that while Adipor1 and Mfrp interact to affect spotting and degeneration, they act independently to control axial length, highlighting the complex functional association between these two genes. Further examination of the molecular basis of this interaction may help in uncovering mechanisms by which these genes perturb ocular homeostasis.<\/jats:p>","DOI":"10.3390\/ijms23031615","type":"journal-article","created":{"date-parts":[[2022,1,31]],"date-time":"2022-01-31T01:46:08Z","timestamp":1643593568000},"page":"1615","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Genetic Interaction between Mfrp and Adipor1 Mutations Affect Retinal Disease Phenotypes"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-4918-0850","authenticated-orcid":false,"given":"Navdeep","family":"Gogna","sequence":"first","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sonia","family":"Weatherly","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1006-6180","authenticated-orcid":false,"given":"Fuxin","family":"Zhao","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"},{"name":"School of Optometry and Ophthalmology and Eye Hospital, Wenzhou Medical University, Wenzhou 325027, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gayle B.","family":"Collin","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jai","family":"Pinkney","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3998-9579","authenticated-orcid":false,"given":"Lisa","family":"Stone","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J\u00fcrgen K.","family":"Naggert","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2834-8186","authenticated-orcid":false,"given":"Gregory W.","family":"Carter","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1640-5945","authenticated-orcid":false,"given":"Patsy M.","family":"Nishina","sequence":"additional","affiliation":[{"name":"The Jackson Laboratory, 600 Main Street, Bar Harbor, ME 04609, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,1,30]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1017\/S0952523808080723","article-title":"Membrane frizzled-related protein is necessary for the normal development and maintenance of photoreceptor outer segments","volume":"25","author":"Won","year":"2008","journal-title":"Vis. Neurosci."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1879","DOI":"10.1093\/hmg\/11.16.1879","article-title":"Mfrp, a gene encoding a frizzled related protein, is mutated in the mouse retinal degeneration 6","volume":"11","author":"Kameya","year":"2002","journal-title":"Hum. Mol. Genet."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"5514","DOI":"10.1167\/iovs.06-0449","article-title":"Spatial and temporal expression of MFRP and its interaction with CTRP5","volume":"47","author":"Mandal","year":"2006","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"16151","DOI":"10.1038\/s41598-017-16275-8","article-title":"Gene Therapy Restores Mfrp and Corrects Axial Eye Length","volume":"7","author":"Velez","year":"2017","journal-title":"Sci. Rep."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"9553","DOI":"10.1073\/pnas.0501451102","article-title":"Extreme hyperopia is the result of null mutations in MFRP, which encodes a Frizzled-related protein","volume":"102","author":"Sundin","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"19986","DOI":"10.1038\/s41598-020-76725-8","article-title":"Novel TMEM98, MFRP, PRSS56 variants in a large United States high hyperopia and nanophthalmos cohort","volume":"10","author":"Prasov","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"805","DOI":"10.1001\/archophthalmol.2011.129","article-title":"Posterior microphthalmos as a genetically heterogeneous condition that can be allelic to nanophthalmos","volume":"129","author":"Aldahmesh","year":"2011","journal-title":"Arch. Ophthalmol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"367","DOI":"10.1089\/hum.2011.169","article-title":"Gene therapy for retinitis pigmentosa caused by MFRP mutations: Human phenotype and preliminary proof of concept","volume":"23","author":"Dinculescu","year":"2012","journal-title":"Hum. Gene. Ther."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"474","DOI":"10.1080\/13816810.2020.1795888","article-title":"A novel MFRP gene variant in a family with posterior microphthalmos, retinitis pigmentosa, foveoschisis, and foveal hypoplasia","volume":"41","author":"Godinho","year":"2020","journal-title":"Ophthalmic Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1016\/j.ajo.2008.04.029","article-title":"A novel mutation confirms MFRP as the gene causing the syndrome of nanophthalmos-renititis pigmentosa-foveoschisis-optic disk drusen","volume":"146","author":"Crespi","year":"2008","journal-title":"Am. J. Ophthalmol."},{"key":"ref_11","first-page":"1483","article-title":"A new autosomal recessive syndrome consisting of posterior microphthalmos, retinitis pigmentosa, foveoschisis, and optic disc drusen is caused by a MFRP gene mutation","volume":"12","author":"Robredo","year":"2006","journal-title":"Mol. Vis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"7256","DOI":"10.1167\/iovs.11-8112","article-title":"174delG mutation in mouse MFRP causes photoreceptor degeneration and RPE atrophy","volume":"52","author":"Fogerty","year":"2011","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"632","DOI":"10.1089\/hum.2018.192","article-title":"Long-Term Effects of Gene Therapy in a Novel Mouse Model of Human MFRP-Associated Retinopathy","volume":"30","author":"Chekuri","year":"2019","journal-title":"Hum. Gene Ther."},{"key":"ref_14","first-page":"2623","article-title":"Membrane frizzled-related protein gene-related ophthalmological syndrome: 30-month follow-up of a sporadic case and review of genotype-phenotype correlation in the literature","volume":"18","author":"Neri","year":"2012","journal-title":"Mol. Vis."},{"key":"ref_15","first-page":"1794","article-title":"Compound heterozygosity for a novel and a recurrent MFRP gene mutation in a family with the nanophthalmos-retinitis pigmentosa complex","volume":"15","author":"Zenteno","year":"2009","journal-title":"Mol. Vis."},{"key":"ref_16","first-page":"3149","article-title":"Retinal degeneration 6 (rd6): A new mouse model for human retinitis punctata albescens","volume":"41","author":"Hawes","year":"2000","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"6228","DOI":"10.1038\/ncomms7228","article-title":"Adiponectin receptor 1 conserves docosahexaenoic acid and promotes photoreceptor cell survival","volume":"6","author":"Rice","year":"2015","journal-title":"Nat. Commun."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"1375","DOI":"10.1007\/s00439-016-1730-2","article-title":"A mutation in ADIPOR1 causes nonsyndromic autosomal dominant retinitis pigmentosa","volume":"135","author":"Zhang","year":"2016","journal-title":"Hum. Genet."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1002\/humu.22940","article-title":"ADIPOR1 Is Mutated in Syndromic Retinitis Pigmentosa","volume":"37","author":"Xu","year":"2016","journal-title":"Hum. Mutat."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/13816810701651241","article-title":"Developmental basis of nanophthalmos: MFRP Is required for both prenatal ocular growth and postnatal emmetropization","volume":"29","author":"Sundin","year":"2008","journal-title":"Ophthalmic Genet."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Koli, S., Labelle-Dumais, C., Zhao, Y., Paylakhi, S., and Nair, K.S. (2021). Identification of MFRP and the secreted serine proteases PRSS56 and ADAMTS19 as part of a molecular network involved in ocular growth regulation. PLoS Genet., 17.","DOI":"10.1371\/journal.pgen.1009458"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"233","DOI":"10.1016\/j.neulet.2012.02.050","article-title":"Adiponectin receptor 1 gene (ADIPOR1) variant is associated with advanced age-related macular degeneration in Finnish population","volume":"513","author":"Kaarniranta","year":"2012","journal-title":"Neurosci. Lett."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"458","DOI":"10.1038\/s41419-021-03741-5","article-title":"ADIPOR1 deficiency-induced suppression of retinal ELOVL2 and docosahexaenoic acid levels during photoreceptor degeneration and visual loss","volume":"12","author":"Osada","year":"2021","journal-title":"Cell Death Dis."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1096\/fj.201902359R","article-title":"Membrane-type frizzled-related protein regulates lipidome and transcription for photoreceptor function","volume":"34","author":"Kautzmann","year":"2020","journal-title":"FASEB J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e9167","DOI":"10.15252\/msb.20199167","article-title":"Genetic interaction profiles of regulatory kinases differ between environmental conditions and cellular states","volume":"16","author":"Sun","year":"2020","journal-title":"Mol. Syst. Biol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"1397","DOI":"10.1091\/mbc.E15-07-0467","article-title":"A genetic interaction map of cell cycle regulators","volume":"27","author":"Billmann","year":"2016","journal-title":"Mol. Biol. Cell"},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Costanzo, M., VanderSluis, B., Koch, E.N., Baryshnikova, A., Pons, C., Tan, G., Wang, W., Usaj, M., Hanchard, J., and Lee, S.D. (2016). A global genetic interaction network maps a wiring diagram of cellular function. Science, 353.","DOI":"10.1126\/science.aaf1420"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"290","DOI":"10.3389\/fgene.2013.00290","article-title":"Genetic interaction networks: Better understand to better predict","volume":"4","author":"Boucher","year":"2013","journal-title":"Front. Genet."},{"key":"ref_29","doi-asserted-by":"crossref","unstructured":"Ang, M., and Wong, T.Y. (2020). Understanding Myopia: Pathogenesis and Mechanisms. Updates on Myopia, Springer.","DOI":"10.1007\/978-981-13-8491-2"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"380","DOI":"10.1093\/bib\/6.4.380","article-title":"Inferring network interactions within a cell","volume":"6","author":"Carter","year":"2005","journal-title":"Brief Bioinform."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1038\/mp.2013.133","article-title":"Epistatic interaction between COMT and DTNBP1 modulates prefrontal function in mice and in humans","volume":"19","author":"Papaleo","year":"2014","journal-title":"Mol. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"355","DOI":"10.1007\/978-1-4614-3209-8_45","article-title":"Subretinal infiltration of monocyte derived cells and complement misregulation in mice with AMD-like pathology","volume":"801","author":"Fogerty","year":"2014","journal-title":"Adv. Exp. Med. Biol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"2190","DOI":"10.1523\/JNEUROSCI.10-07-02190.1990","article-title":"Docosahexaenoic acid utilization during rod photoreceptor cell renewal","volume":"10","author":"Gordon","year":"1990","journal-title":"J. Neurosci."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"73","DOI":"10.3109\/02713689209069169","article-title":"Retinal pigment epithelial cells play a central role in the conservation of docosahexaenoic acid by photoreceptor cells after shedding and phagocytosis","volume":"11","author":"Gordon","year":"1992","journal-title":"Curr. Eye Res."},{"key":"ref_35","first-page":"2402","article-title":"Visualization of [3H]docosahexaenoic acid trafficking through photoreceptors and retinal pigment epithelium by electron microscopic autoradiography","volume":"34","author":"Gordon","year":"1993","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"100058","DOI":"10.1194\/jlr.TR120001137","article-title":"Overview of how N32 and N34 elovanoids sustain sight by protecting retinal pigment epithelial cells and photoreceptors","volume":"62","author":"Bazan","year":"2021","journal-title":"J. Lipid Res."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"14339","DOI":"10.1038\/s41598-018-32579-9","article-title":"ADIPOR1 is essential for vision and its RPE expression is lost in the Mfrp(rd6) mouse","volume":"8","author":"Sluch","year":"2018","journal-title":"Sci. Rep."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1289","DOI":"10.1038\/s41598-019-57338-2","article-title":"The majority of autosomal recessive nanophthalmos and posterior microphthalmia can be attributed to biallelic sequence and structural variants in MFRP and PRSS56","volume":"10","author":"Almoallem","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"6805","DOI":"10.1167\/iovs.16-19593","article-title":"Loss of Zebrafish Mfrp Causes Nanophthalmia, Hyperopia, and Accumulation of Subretinal Macrophages","volume":"57","author":"Collery","year":"2016","journal-title":"Investig. Ophthalmol. Vis. Sci."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"60","DOI":"10.4161\/org.4.2.5850","article-title":"Wnt signaling in eye organogenesis","volume":"4","author":"Fuhrmann","year":"2008","journal-title":"Organogenesis"},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"116","DOI":"10.1006\/bbrc.2001.4551","article-title":"Molecular cloning and characterization of MFRP, a novel gene encoding a membrane-type Frizzled-related protein","volume":"282","author":"Katoh","year":"2001","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"395","DOI":"10.1007\/978-1-4939-3661-8_20","article-title":"Bright-Field Imaging and Optical Coherence Tomography of the Mouse Posterior Eye","volume":"1438","author":"Krebs","year":"2016","journal-title":"Methods Mol. Biol"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"Fiji: An open-source platform for biological-image analysis","volume":"9","author":"Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"99","DOI":"10.1097\/00006324-200402000-00008","article-title":"Measurement of refractive state and deprivation myopia in two strains of mice","volume":"81","author":"Schaeffel","year":"2004","journal-title":"Optom. Vis. Sci."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1615\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:11:33Z","timestamp":1760134293000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/23\/3\/1615"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,1,30]]},"references-count":44,"journal-issue":{"issue":"3","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["ijms23031615"],"URL":"https:\/\/doi.org\/10.3390\/ijms23031615","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,1,30]]}}}