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EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma
Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, United States; Department of Ophthalmology, Manila Doctors Hospital, Manila, Philippines.
Department of Ophthalmology, Manila Doctors Hospital, Manila, Philippines.
Department of Ophthalmology, Massachusetts Eye and Ear, Harvard Medical School, Boston, United States.
Department of Ophthalmology, Cebu Institute of Medicine, Cebu Velez General Hospital, Cebu City, Philippines.
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2022 (English)In: Human Mutation, ISSN 1059-7794, E-ISSN 1098-1004, Vol. 43, no 2, p. 240-252Article in journal (Refereed) Published
Abstract [en]

Juvenile open-angle glaucoma (JOAG) is a severe type of glaucoma with onset before age 40 and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with novel EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C, p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cys) co-segregating with disease. Affected variant carriers (N = 34) exhibited severe disease with average age of onset of 16 years and with 76% developing blindness. To investigate functional effects, we transfected COS7 cells with vectors expressing the three novel EFEMP1 variants and showed that all three variants found in JOAG patients caused significant intracellular protein aggregation and retention compared to wild type and also compared to EFEMP1 variants associated with other ocular phenotypes including an early-onset form of macular degeneration, Malattia Leventinese/Doyne's Honeycomb retinal dystrophy. These results suggest that rare EFEMP1 coding variants can cause JOAG through a mechanism involving protein aggregation and retention, and that the extent of intracellular retention correlates with disease phenotype. This is the first report of EFEMP1 variants causing JOAG, expanding the EFEMP1 disease spectrum. Our results suggest that EFEMP1 mutations appear to be a relatively common cause of JOAG in Filipino families, an ethnically diverse population.

Place, publisher, year, edition, pages
John Wiley & Sons, 2022. Vol. 43, no 2, p. 240-252
National Category
Medical Genetics Ophthalmology
Identifiers
URN: urn:nbn:se:umu:diva-191094DOI: 10.1002/humu.24320ISI: 000734990000001PubMedID: 34923728Scopus ID: 2-s2.0-85122015862OAI: oai:DiVA.org:umu-191094DiVA, id: diva2:1626224
Funder
NIH (National Institute of Health), P30EY014104NIH (National Institute of Health), R01 EY031830
Note

Errata: Collantes, E.R.A., Delfin, M.S., Fan, B., Torregosa, J.M.R., Siguan-Bell, C., Vincent de Guzman Florcruz, N., Martinez, J.M.D., Joy Masna-Hidalgo, B., Guzman, V.P.T., Anotado-Flores, J.F., Levina, F.D., Hernandez, S.R.C., Collantes, A.A., Sibulo, M.C., Rong, S. and Wiggs, J.L. (2022), EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma. Human Mutation. DOI: 10.1002/humu.24395.

Available from: 2022-01-11 Created: 2022-01-11 Last updated: 2022-10-31Bibliographically approved

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Hernandez, Sophia Raine C.

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