Congenital Achromatopsia and Macular Atrophy Caused by a Novel Recessive PDE6C Mutation (p.E591K)

Abstract

Purpose: We have previously reported clinical features of two siblings, a sister with complete achromatopsia (ACHM) and a brother with incomplete ACHM, in a consanguineous Japanese family. With the current study, we intended to identify a disease-causing mutation in the siblings and to investigate why the phenotypes of the siblings differed.

Methods: We performed a comprehensive ophthalmic examination for each sibling and parent. Whole-exome and Sanger sequencing were performed on genomic DNA. Molecular modeling was analyzed in an in silico study.

Results: The ophthalmic examination revealed severe macular atrophy in the older female sibling at 30 years of age and mild macular atrophy in the brother at 26 years of age. The genetic analysis identified a novel homozygous PDE6C mutation (p.E591K) as the disease-causing allele in the siblings. Each parent was heterozygous for the mutation. Molecular modeling showed that the mutation could cause a conformational change in the PDE6C protein and result in reduced phosphodiesterase activity. We also identified an OPN1SW mutation (p.G79R), which is associated with congenital tritan deficiencies, in the sister and the father but not in the brother.

Conclusions: A novel homozygous PDE6C mutation was identified as the cause of ACHM. In addition, we identified an OPN1SW mutation in the sibling with complete ACHM, which might explain the difference in phenotype (complete versus incomplete ACHM) between the siblings.

• Achromatopsia
• OPN1SW
• PDE6C
• RHO
• whole-exome sequencing

ACKNOWLEDGEMENTS

We thank the patients and their families for participation in this study.

The authors wish to acknowledge RIKEN GeNAS for the sequencing of the exome-enriched libraries using Illumina HiSeq2000.

DECLARATION OF INTEREST

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.

This work was supported by grants to T.I. from the Ministry of Health, Labor and Welfare of Japan [13803661], to M.A. and T.H. from the Ministry of Education, Culture, Sports, Science and Technology of Japan [Grant-in-Aid for Scientific Research C, 25462744 and 25462738], and to M.F. from the Research Grant for RIKEN Omics Science Center MEXT.

Supplementary Material Available Online

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