Autosomal-dominant macular dystrophy linked to a chromosome 17 tandem duplication
Hereditary macular dystrophies (HMDs) are a genetically diverse group of disorders that cause central vision loss due to photoreceptor and retinal pigment epithelium (RPE) damage. We investigated a family with a presumed novel autosomal-dominant HMD characterized by faint, hypopigmented RPE changes involving the central retina. Genome and RNA sequencing identified the disease-causing variant to be a 560 kb tandem duplication on chromosome 17 [NC_000017.10 (hg19): g.4012590_4573014dup], which led to the formation of a novel ZZEF1-ALOX15 fusion gene, which upregulates ALOX15. ALOX15 encodes a lipoxygenase involved in polyunsaturated fatty acid metabolism. Functional studies showed retinal disorganization and photoreceptor and RPE damage following electroporation of the chimera transcript in mouse retina. Photoreceptor damage also occurred following electroporation with a native ALOX15 transcript but not with a near-null ALOX15 transcript. Affected patients' lymphoblasts demonstrated lower levels of ALOX15 substrates and an accumulation of neutral lipids. We implicated the fusion gene as the cause of this family's HMD, due to mislocalization and overexpression of ALOX15, driven by the ZZEF1 promoter. To our knowledge, this is the first reported instance of a fusion gene leading to HMD or inherited retinal dystrophy, highlighting the need to prioritize duplication analysis in unsolved retinal dystrophies.
Authors
- Christabel Eileen
- Rowaida Hussein
- Xiaoyan Chen (ORCID: https://orcid.org/0000-0003-3719-6601)
- Simon Monis
- Philippe P. Monnier (ORCID: https://orcid.org/0000-0002-6221-4130)
- Erika Tavares (ORCID: https://orcid.org/0000-0002-5714-1766)
- Matteo Di Scipio (ORCID: https://orcid.org/0000-0001-6280-3739)
- Nicole M. Roslin (ORCID: https://orcid.org/0000-0002-4609-8299)
- Jason Charish
- Nishanth E. Sunny (ORCID: https://orcid.org/0000-0003-1607-2095)
- Raju V. S. Rajala (ORCID: https://orcid.org/0000-0003-3783-8504)
- Evgueni A. Ivakine (ORCID: https://orcid.org/0000-0003-2132-4699)
- Andrew D. Paterson (ORCID: https://orcid.org/0000-0002-9169-118X)
- Eric I. Campos (ORCID: https://orcid.org/0000-0001-8152-3994)
- Tara Paton (ORCID: https://orcid.org/0000-0003-3212-0173)
- Jason T. Maynes (ORCID: https://orcid.org/0000-0002-2050-3620)
- Michael D. Wilson (ORCID: https://orcid.org/0000-0002-6048-8509)
- Minggao Liang
- Elise Héon (ORCID: https://orcid.org/0000-0003-4143-9311)
- Ajoy Vincent (ORCID: https://orcid.org/0000-0001-6446-3846)
- Anupreet Tumber
- Kashif Ahmed (ORCID: https://orcid.org/0000-0001-7370-1148)
- Rabiat Adele
Institutions
- University of Toronto (CA)
- Toronto Western Hospital (CA)
- Hospital for Sick Children (CA)
- Ontario Genomics (CA)
- Dean McGee Eye Institute (US)
- Krembil Foundation (CA)
- SickKids Foundation (CA)
- Institute of Molecular Medicine (IN)
- Pain and Rehabilitation Medicine (US)
- Krembil Research Institute
- University of Oklahoma Health Sciences Center (US)
- University of Maryland, College Park (US)
Publication Details
- Journal
- JCI Insight
- Published
- 2024-10-22
- DOI
- https://doi.org/10.1172/jci.insight.178768
- Primary Topic
- Retinal Development and Disorders
- Type
- article
- Field-Weighted Citation Impact
- 0.00