期刊名称：Proceedings of the National Academy of Sciences
印刷版ISSN：0027-8424
电子版ISSN：1091-6490
出版年度：2022
卷号：119
期号：27
DOI：10.1073/pnas.2115538119
语种：English
出版社：The National Academy of Sciences of the United States of America
摘要：Significance
Blue cone monochromacy (BCM) is an inherited retinal disorder characterized by low vision and poor color vision and caused by mutations in the multicopy gene cluster encoding the long- and middle-wavelength-sensitive cone photoreceptor visual pigments. We showed that structural genomic mutations at the gene cluster explain about one-third of those affected among 213 genetically confirmed BCM families. Our study expands the known spectrum of structural mutations causing BCM by a factor of 4 and provides a comprehensive landscape of their extent and fine structure as well as a deep insight into the underlying molecular mechanisms. We observed evidence that occurrence of BCM-linked structural mutations may be driven by inherent increased instability of individual gene clusters with large copy numbers.
Blue cone monochromacy (BCM) is an X-linked retinal disorder characterized by low vision, photoaversion, and poor color discrimination. BCM is due to the lack of long-wavelength-sensitive and middle-wavelength-sensitive cone photoreceptor function and caused by mutations in the
OPN1LW/OPN1MW gene cluster on Xq28. Here, we investigated the prevalence and the landscape of submicroscopic structural variants (SVs) at single-base resolution in BCM patients. We found that about one-third (
n = 73) of the 213 molecularly confirmed BCM families carry an SV, most commonly deletions restricted to the
OPN1LW/OPN1MW gene cluster. The structure and precise breakpoints of the SVs were resolved in all but one of the 73 families. Twenty-two families—all from the United States—showed the same SV, and we confirmed a common ancestry of this mutation. In total, 42 distinct SVs were identified, including 40 previously unreported SVs, thereby quadrupling the number of precisely mapped SVs underlying BCM. Notably, there was no “region of overlap” among these SVs. However, 90% of SVs encompass the upstream locus control region, an essential enhancer element. Its minimal functional extent based on deletion mapping in patients was refined to 358 bp. Breakpoint analyses suggest diverse mechanisms underlying SV formation as well as in one case the gene conversion-based exchange of a 142-bp deletion between opsin genes. Using parsimonious assumptions, we reconstructed the composition and copy number of the
OPN1LW/OPN1MW gene cluster prior to the mutation event and found evidence that large gene arrays may be predisposed to the occurrence of SVs at this locus.
关键词：enhuman visual pigment genesBCMopsin gene deletiongene conversionlocus control region
