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Single-base substitutions in the CHM promoter as a cause of choroideremia

Radziwon, A; Arno, G; Wheaton, DK; McDonagh, EM; Baple, EL; Webb-Jones, K; Birch, DG; ... MacDonald, IM; + view all (2017) Single-base substitutions in the CHM promoter as a cause of choroideremia. Human Mutation , 38 (6) pp. 704-715. 10.1002/humu.23212. Green open access

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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.

Type: Article
Title: Single-base substitutions in the CHM promoter as a cause of choroideremia
Location: Seattle, WA
Open access status: An open access version is available from UCL Discovery
DOI: 10.1002/humu.23212
Publisher version: http://dx.doi.org/10.1002/humu.23212
Language: English
Additional information: This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions.
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > Institute of Ophthalmology
URI: https://discovery-pp.ucl.ac.uk/id/eprint/10044279
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