Single‐base substitutions in the CHM promoter as a cause of choroideremia. Issue 6 (24th March 2017)

• Record Type: Journal Article
• Authors: Radziwon, Alina; Arno, Gavin; K. Wheaton, Dianna; McDonagh, Ellen M.; Baple, Emma L.; Webb‐Jones, Kaylie; G. Birch, David; Webster, Andrew R.; MacDonald, Ian M.
• Is Part Of: Human mutation. Volume 38:Issue 6(2017)
• Page Start: 704
• Page End: 715
• Publication Date: 2017-03-24
• Subjects: CHM -- choroideremia -- promoter -- REP‐1 -- THAP11 -- ZNF143; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23212
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : Mutations in the previously unidentified CHM promoter result in choroideremia (CHM), characterized by progressive chorioretinal atrophy and vision loss. We report the first two mutations outside the gene's coding sequence causing CHM, at position c.−98: C>A and C>T. Both mutations abrogated luciferase activity in a promoter reporter construct, while a cell line from a patient bearing the mutation failed to express CHM mRNA. Additionally, full genome sequencing in a second patient excluded the involvement of any other known retinal gene. 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.