title: Single-base substitutions in the CHM promoter as a cause of choroideremia.
abstract: Although over 150 unique mutations affecting the coding sequence of CHM have been identified in patients with the X-linked chorioretinal disease choroideremia (CHM), no regulatory mutations have been reported, and indeed the promoter has not been defined. Here, we describe two independent families affected by CHM bearing a mutation outside the gene's coding region at position c.-98: C>A and C>T, which segregated with the disease. The male proband of family 1 was found to lack CHM mRNA and its gene product Rab escort protein 1, whereas whole-genome sequencing of an affected male in family 2 excluded the involvement of any other known retinal genes. Both mutations abrogated luciferase activity when inserted into a reporter construct, and by further employing the luciferase reporter system to assay sequences 5' to the gene, we identified the CHM promoter as the region encompassing nucleotides c.-119 to c.-76. These findings suggest that the CHM promoter region should be examined in patients with CHM who lack coding sequence mutations, and reveals, for the first time, features of the gene's regulation.
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Alina
authors.initials: A
authors.lastname: Radziwon
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Gavin
authors.initials: G
authors.lastname: Arno
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Dianna
authors.initials: D
authors.lastname: K Wheaton
authors.affiliation: Genomics England, Queen Mary University of London, London, UK.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: McDonagh
authors.affiliation: Genomics England, Queen Mary University of London, London, UK.|Medical Research (Level 4), RILD Wellcome Wolfson Centre, Royal Devon and Exeter NHS Foundation Trust, University of Exeter Medical School, Exeter, UK.
authors.forename: Emma L
authors.initials: EL
authors.lastname: Baple
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: Kaylie
authors.initials: K
authors.lastname: Webb-Jones
authors.affiliation: Retina Foundation of the Southwest, Dallas, Texas.
authors.forename: David
authors.initials: D
authors.lastname: G Birch
authors.affiliation: UCL Institute of Ophthalmology, University College London, London, UK.|Moorfields Eye Hospital, London, UK.
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
authors.affiliation: Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Canada.
authors.forename: Ian M
authors.initials: IM
authors.lastname: MacDonald
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D015794:Choroideremia / Q000150:complications / Q000235:genetics* / Q000473:pathology; D005260:Female; D040181:Genetic Diseases, X-Linked; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D009154:Mutation; D010375:Pedigree; D011401:Promoter Regions, Genetic / Q000235:genetics; D012160:Retina / Q000378:metabolism / Q000473:pathology; D012162:Retinal Degeneration / Q000150:complications / Q000235:genetics* / Q000473:pathology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C081787:CHM protein, human
keywords: CHM; REP-1; THAP11; ZNF143; choroideremia; promoter