Autosomal dominant macular dystrophy linked to a chromosome 17 tandem duplication.

Autor:	Adele R; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Hussein R; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Tavares E; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Ahmed K; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Di Scipio M; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Charish J; Vision Division, Krembil Research Institute, Toronto, Canada., Liang M; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Monis S; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Tumber A; Department of Ophthalmology and Visual Sciences, Hospital for Sick Children, Toronto, Canada., Chen X; Vision Division, Krembil Research Institute, Toronto, Canada., Paton TA; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Roslin NM; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Eileen C; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Ivakine E; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Sunny NE; Department of Animal and Avian Sciences, University of Maryland, College Park, United States of America., Wilson MD; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Campos E; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Rajala RV; Departments of Ophthalmology, Physiology, and Cell Biology, and Dean McGee, University of Oklahoma Health Sciences Center, Oklahoma City, United States of America., Maynes JT; Department of Anesthesia and Pain Medicine, Hospital for Sick Children, Toronto, Canada., Monnier PP; Vision Division, Krembil Research Institute, Toronto, Canada., Paterson AD; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Héon E; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada., Vincent A; Genetics and Genome Biology, Hospital for Sick Children, Toronto, Canada.
Jazyk:	angličtina
Zdroj:	JCI insight [JCI Insight] 2024 Oct 22. Date of Electronic Publication: 2024 Oct 22.
DOI:	10.1172/jci.insight.178768
Abstrakt:	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 kilobase tandem duplication on chromosome 17 [NC_000017.10 (hg19): g.4012590_4573014dup], which led to the formation of a novel ZZEF1-ALOX15 fusion gene, that 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 mis-localization 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.
Databáze:	MEDLINE
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