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Invest Ophthalmol Vis Sci. 2014 Oct 14;55(11):7159-64. doi: 10.1167/iovs.14-15520.

A missense mutation in HK1 leads to autosomal dominant retinitis pigmentosa.

Author information

1
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States.
2
Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, China.
3
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States.
4
Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States.
5
Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah School of Medicine, Salt Lake City, Utah, United States.
6
Shiley Eye Center and Institute for Genomic Medicine, University of California-San Diego, La Jolla, California, United States Veterans Administration Healthcare System, San Diego, California, United States.
7
Human Genome Sequencing Center, Baylor College of Medicine, Houston, Texas, United States Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States Structural and Computational Biology and Molecular Biophysics Graduate Program, Baylor College of Medicine, Houston, Texas, United States The Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas, United States Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States.

Abstract

PURPOSE:

Retinitis pigmentosa (RP) is a genetically heterogeneous disease with over 60 causative genes known to date. Nevertheless, approximately 40% of RP cases remain genetically unsolved, suggesting that many novel disease-causing genes are yet to be identified. In this study, we aimed to identify the causative mutation for a large autosomal dominant RP (adRP) family with negative results from known retinal disease gene screening.

METHODS:

Linkage analysis followed by whole-exome sequencing was performed. Stringent variant filtering and prioritization was carried out to identify the causative mutation.

RESULTS:

Linkage analysis identified a minimal disease region of 8 Mb on chromosome 10 with a peak parametric logarithm (base 10) of odds (LOD) score of 3.500. Further whole-exome sequencing identified a heterozygous missense mutation (NM_000188.2:c.2539G>A, p.E847K) in hexokinase 1 (HK1) that segregated with the disease phenotype in the family. Biochemical assays showed that the E847K mutation does not affect hexokinase enzymatic activity or the protein stability, suggesting that the mutation may impact other uncharacterized function or result in a gain of function of HK1.

CONCLUSIONS:

Here, we identified HK1 as a novel causative gene for adRP. This is the first report that associates the glucose metabolic pathway with human retinal degenerative disease, suggesting a potential new disease mechanism.

KEYWORDS:

HK1; autosomal dominant retinitis pigmentosa (adRP); hexokinase; next-generation sequencing (NGS); novel disease-causing gene

PMID:
25316723
PMCID:
PMC4224578
DOI:
10.1167/iovs.14-15520
[Indexed for MEDLINE]
Free PMC Article

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