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Hum Mol Genet. 2018 Dec 1;27(23):4157-4168. doi: 10.1093/hmg/ddy281.

Whole-exome sequencing revealed HKDC1 as a candidate gene associated with autosomal-recessive retinitis pigmentosa.

Zhang L1,2, Sun Z3, Zhao P4, Huang L1, Xu M5,6, Yang Y1, Chen X7, Lu F1, Zhang X4, Wang H8, Zhang S1, Liu W1, Jiang Z1,9, Ma S1,9, Chen R5,6, Zhao C7,10,11, Yang Z1,9,12, Sui R3, Zhu X1,13,9,12,2.

Author information

Sichuan Provincial Key Laboratory for Human Disease Gene Study, Sichuan Provincial People's Hospital, School of Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Center of Information in Medicine, University of Electronic Science and Technology of China, Chengdu, Sichuan, China.
Department of Ophthalmology, Peking Union Medical College Hospital, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, China.
Department of Ophthalmology, Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine, Shanghai, China.
Department of Molecular and Human Genetics.
Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX, USA.
Department of Ophthalmology, Hospital of Nanjing Medical University, State Key Laboratory of Reproductive Medicine, Nanjing, China.
Institute of Life Sciences, Hangzhou Normal University, Hangzhou, Zhejiang, China.
Institute of Laboratory Medicine, SichuanAcademy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, China.
Department of Ophthalmology and Vision Science, Eye & ENT Hospital, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Ophthalmology, Children's Hospital of Zhengzhou, Zhengzhou, China.
Chinese Academy of Sciences Sichuan Translational Medicine Hospital, Institute of Chengdu Biology Chengdu, China.
Institute of Laboratory Animal Sciences, Sichuan Academy of Medical Sciences and Sichuan Provincial People's Hospital, Chengdu, Sichuan, China.


Retinitis pigmentosa (RP) is an inheritable retina degenerative disease leading to blindness. Despite the identification of 70 genes associated with RP, the genetic cause of ∼40% of RP patients remains to be elucidated. Whole-exome sequencing was applied on the probands of a RP cohort of 68 unsolved cases to identify candidate genetic mutations. A homozygous missense variant (c.173C > T, p.T58 M) was found in HKDC1 in two unrelated families presenting late-onset retinal degeneration. This variant affects highly conserved amino acid residue and is very rare in several databases and absent in 4000 ethnic-matched controls. Mutant HKDC1 protein partially lost hexokinase activity. Hkdc1 is expressed in the mouse retina and localized to photoreceptor inner segments. To elucidate the in vivo roles of Hkdc1 in the retina, we generated Hkdc1 knockout (KO) mouse models using CRISPR/Cas9 technique. Two independent alleles were identified and backcrossed to C57BL/6 J for 6 generations. Absence of HKDC1 expression in the Hkdc1 KO retina was confirmed by western blot and immunostaning using HKDC1 antibody. Hkdc1 KO mice exhibited reduced scotopic electroretinogram response and thinner outer nuclear layer, similar to some of the human patient phenotypes. Loss of Hkdc1 led to mislocalization of rhodopsin to the inner segments and cell bodies of rods in some regions in the retina. Taken together, our data demonstrated that HKDC1 is associated with autosomal recessively inherited RP.

[Available on 2019-12-01]

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