Taylor, RL; Poulter, JA; Downes, SM; McKibbin, M; Khan, KN; Inglehearn, CF; Webster, AR; ... UKIRDC; + view all Taylor, RL; Poulter, JA; Downes, SM; McKibbin, M; Khan, KN; Inglehearn, CF; Webster, AR; Hardcastle, AJ; Michaelides, M; Bishop, PN; Clark, SJ; Black, GC; UKIRDC; - view fewer (2019) Loss-of-function mutations in the CFH gene affecting alternatively encoded Factor H-like 1 protein cause dominant early-onset macular drusen. Ophthalmology , 126 (10) pp. 1410-1421. 10.1016/j.ophtha.2019.03.013.

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Abstract

Purpose To characterise the molecular mechanism underpinning early-onset macular drusen (EOMD), a phenotypically severe sub-type of age-related macular degeneration (AMD), in a sub-group of patients. Design Multi-centre case series, in vitro experimentation and retrospective analysis of previously reported variants. Participants Seven families with apparently autosomal dominant EOMD. Methods Patients underwent comprehensive ophthalmic assessment. Affected individuals from families A, B and E underwent whole exome sequencing. The probands from families C, D, F and G underwent Sanger sequencing analysis of the Complement Factor H (CFH) gene. Mutant recombinant Factor H Like-1 (FHL-1) proteins were expressed in HEK293 cells to assess the impact on FHL-1 expression and function. Previously reported EOMD-causing variants in CFH were reviewed. Main Outcome Measures Detailed clinical phenotypes, genomic findings, in vitro characterization of mutation effect on protein function, and postulation of the pathomechanism underpinning EOMD. Results All affected participants presented with bilateral drusen. The earliest reported age of onset was 16 years with a median of 46 years). Ultra-rare (MAF ≤0.0001) CFH variants were identified as the cause of disease in each family: CFH c.1243del, p.(Ala415ProfsTer39) het; c.350+1G>T het; c.619+1G>A het, c.380G>A, p.(Arg127His) het; c.694C>T p.(Arg232Ter)het [identified in two unrelated families in this cohort]; and c.1291T>A, p.(Cys431Ser). All mutations affect complement control protein domains (CCP) 2-7, thus are predicted to impact both FHL-1, the predominant isoform in Bruch’s membrane(BrM) of the macula, and FH. In vitro analysis of recombinant proteins FHL-1R127H, FHL-1A415f/s and FHL-1C431S demonstrated that they are not secreted and thus are loss-of-function. Intra-cellular expression of mutant proteins was low, suggesting they may be rapidly degraded due to protein unfolding or instability. Review of 29 previously reported EOMD-causing mutations found that 75.8% (22/29) of impact FHL-1 and FH. In total, 86.2% (25/29) EOMD-associated variants cause haploinsufficiency of FH/FHL-1. Conclusions EOMD is an under-recognised, phenotypically severe sub-type of AMD. We propose that haploinsufficiency of FHL-1, the main regulator of the complement pathway in BrM, where drusen develop, is an important mechanism underpinning the development of EOMD in a number of cases. Understanding the molecular basis of EOMD will shed light on AMD pathogenesis given their pathological similarities.

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