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

ABSTRACT: 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.

SUBMITTER: Zhang L

PROVIDER: S-EPMC6240732 | biostudies-literature | 2018 Dec

REPOSITORIES: biostudies-literature

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

Zhang Lin L Sun Zixi Z Zhao Peiquan P Huang Lulin L Xu Mingchu M Yang Yeming Y Chen Xue X Lu Fang F Zhang Xiang X Wang Hui H Zhang Shanshan S Liu Wenjing W Jiang Zhilin Z Ma Shi S Chen Rui R Zhao Chen C Yang Zhenglin Z Sui Ruifang R Zhu Xianjun X

Human molecular genetics 20181201 23

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 varian ...[more]

PMID: 30085091

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Project description:PURPOSE: Retinitis pigmentosa (RP) is an inherited retinal dystrophy characterized by extreme genetic and clinical heterogeneity. Thus, the diagnosis is not always easily performed due to phenotypic and genetic overlap. Current clinical practices have focused on the systematic evaluation of a set of known genes for each phenotype, but this approach may fail in patients with inaccurate diagnosis or infrequent genetic cause. In the present study, we investigated the genetic cause of autosomal recessive RP (arRP) in a Spanish family in which the causal mutation has not yet been identified with primer extension technology and resequencing. METHODS: We designed a whole-exome sequencing (WES)-based approach using NimbleGen SeqCap EZ Exome V3 sample preparation kit and the SOLiD 5500×l next-generation sequencing platform. We sequenced the exomes of both unaffected parents and two affected siblings. Exome analysis resulted in the identification of 43,204 variants in the index patient. All variants passing filter criteria were validated with Sanger sequencing to confirm familial segregation and absence in the control population. In silico prediction tools were used to determine mutational impact on protein function and the structure of the identified variants. RESULTS: Novel Usher syndrome type 2A (USH2A) compound heterozygous mutations, c.4325T>C (p.F1442S) and c.15188T>G (p.L5063R), located in exons 20 and 70, respectively, were identified as probable causative mutations for RP in this family. Family segregation of the variants showed the presence of both mutations in all affected members and in two siblings who were apparently asymptomatic at the time of family ascertainment. Clinical reassessment confirmed the diagnosis of RP in these patients. CONCLUSIONS: Using WES, we identified two heterozygous novel mutations in USH2A as the most likely disease-causing variants in a Spanish family diagnosed with arRP in which the cause of the disease had not yet been identified with commonly used techniques. Our data reinforce the clinical role of WES in the molecular diagnosis of highly heterogeneous genetic diseases where conventional genetic approaches have previously failed in achieving a proper diagnosis.

Dataset Information

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

Publications

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

Similar Datasets

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