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EFEMP1 rare variants cause juvenile-onset open angle glaucoma in families from the Philippines
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  • Edward Collantes,
  • Manuel Delfin ,
  • Bao Jian Fan,
  • Justine Torregosa,
  • Christine Siguan-Bell,
  • Nilo Florcruz,
  • Jose Martinez ,
  • Barbara Masna-Hidalgo,
  • Vincent Guzman,
  • Jewel Anotado-Flores,
  • Faye Levina,
  • Sophia Hernandez,
  • Anthony Collantes,
  • Michael Sibulo,
  • Shisong Rong,
  • Janey Wiggs
Edward Collantes
Harvard Medical School
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Manuel Delfin
Manila Doctors Hospital
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Bao Jian Fan
Harvard Medical School
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Justine Torregosa
Cebu Institute of Medicine
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Christine Siguan-Bell
Cebu Institute of Medicine
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Nilo Florcruz
University of the Philippines Manila
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Jose Martinez
East Avenue Medical Center
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Barbara Masna-Hidalgo
Western Visayas Medical Center
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Vincent Guzman
Western Visayas Medical Center
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Jewel Anotado-Flores
Western Visayas Medical Center
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Faye Levina
Jose R Reyes Memorial Medical Center
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Sophia Hernandez
Umeå Universitet Medicinska fakulteten
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Anthony Collantes
Our Lady of Fatima University College of Medicine
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Michael Sibulo
University of Santo Tomas Faculty of Medicine and Surgery
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Shisong Rong
Harvard Medical School
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Janey Wiggs
Harvard Medical School
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Abstract

Juvenile open angle glaucoma (JOAG) is a severe type of glaucoma with childhood onset and dominant inheritance. Using exome sequencing we identified 3 independent families from the Philippines with rare EFEMP1 variants (c.238A>T, p.Asn80Tyr; c.1480T>C p.Ter494Glnext*29; and c.1429C>T, p.Arg477Cysteine ) 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.

Peer review status:IN REVISION

10 Jul 2021Submitted to Human Mutation
11 Jul 2021Assigned to Editor
11 Jul 2021Submission Checks Completed
19 Jul 2021Reviewer(s) Assigned
09 Aug 2021Review(s) Completed, Editorial Evaluation Pending
22 Aug 2021Editorial Decision: Revise Minor