EFEMP1 rare variants cause familial juvenile-onset open-angle glaucoma.

Abstract

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.

• Authors: Edward Ryan A Collantes, Manuel S Delfin, Baojian Fan, Justine May R Torregosa, Christine Siguan-Bell, Nilo Vincent de Guzman Florcruz, Jose Maria D Martinez, Barbara Joy Masna-Hidalgo, Vincent Paul T Guzman, Jewel Faith Anotado-Flores, Faye D Levina, Sophia Raine C Hernandez, Anthony A Collantes, Michael Carreon Sibulo, Shisong Rong, Janey L Wiggs
• Journal: Human mutation (Hum Mutat) Vol. 43 Issue 2 Pg. 240-252 (02 2022) ISSN: 1098-1004 [Electronic] United States
• PMID: 34923728 (Publication Type: Journal Article)
• Copyright: © 2021 Wiley Periodicals LLC.

Chemical References

• EFEMP1 protein, human
• Extracellular Matrix Proteins

Topics

• Extracellular Matrix Proteins (genetics, metabolism)
• Glaucoma, Open-Angle (genetics, metabolism)
• Heterozygote
• Humans
• Macular Degeneration (genetics, metabolism)
• Mutation