Daiki Kubota, Kaori Matsumoto, Mika Hayashi, Noriko Oishi, Kiyoko Gocho, Kunihiko Yamaki, Shinichiro Kobayakawa, Tsutomu Igarashi, Hiroshi Takahashi, Shuhei Kameya | Ophthalmic Genetics | 20 Aug 2020 | 41(6) | pgs. 629–638 | doi.org/10.1080/13816810.2020.1810284
Abstract
Purpose
The hexokinase 1 (HK1) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism. Recently, several cases of E847K mutation in the HK1 gene were reported to cause inherited retinal dystrophy. The purpose of this study was to identify the phenotypical characteristics of patients with a recurrent E847K mutation in the HK1 gene.
Methods
Three generations of one family with autosomal dominant retinitis pigmentosa were examined. Whole exome sequencing was performed on the DNA. Fundus imaging by an adaptive optics fundus camera was used to obtain high-resolution photoreceptor images.
Results
Fundus examination of the proband showed degeneration of the mid-peripheral retina, and SD-OCT images showed an absence of the ellipsoid zone (EZ) and interdigitation zone (IZ) in the parafovea and more peripherally. SD-OCT images of the mother of the proband showed an absence of the EZ and IZ, and fundus autofluorescence images showed hypo-autofluorescence surrounding the macular region. One daughter of the proband had only mild night blindness, however, the density of the cone photoreceptors was reduced in the parafoveal region. Whole exome sequencing identified a heterozygous variant, E847K, in the HK1 gene. This variant was found to co-segregate with the disease in three family members.
Conclusions
Although the systemic phenotypes were found to be associated with the HK1 mutations, only the E847K mutation can cause a non-syndromic photoreceptor degeneration. Our study strengthened the hypothesis that the amino acid E847 might play a critical role in the maintenance of the morphology and function of the photoreceptors.
Introduction
The hexokinase 1 (HK1; OMIM 14260) gene encodes one of the four human hexokinases that play essential roles in glucose metabolism (Citation1–3). Hexokinase catalyzes the first step in glucose metabolism using ATP for the phosphorylation of glucose to glucose-6-phosphate. Four different forms of hexokinase, HK1, HK2, HK3, and HK4 that are encoded by different genes, are present in mammalian tissues (Citation3). Among these, HK1 is the most ubiquitously expressed and is the predominant hexokinase in the brain, erythrocytes, lymphocytes, and fibroblasts (Citation1). A proteomic study of rats found that HK1 and HK2 are expressed in the retina (Citation4). HK1 was found to be strongly expressed in the photoreceptor inner segment and in the outer plexiform layer, inner nuclear layer, inner plexiform layer, and ganglion cell layer (Citation4).
Thus far, four phenotypes that are associated with HK1 mutations have been listed in the OMIM database (Citation5). They are nonspherocytic hemolytic anemia (NSHA) due to hexokinase deficiency (OMIM; 235700), Russe type of hereditary motor and sensory neuropathy (HMSNR, OMIM; 605285), retinitis pigmentosa 79 (RP79, OMIM; 617460), and neurodevelopmental disorder with visual defects and brain anomalies (NEDVIBA, OMIM; 618547). NSHA, due to hexokinase deficiency, and the Russe type of HMSNR are autosomal recessive inheritance disorders that are caused by homozygous or compound heterozygous loss-of function mutations of the HK1 gene (Citation6–8). On the other hand, five families of autosomal dominant retinitis pigmentosa (adRP; RP79) were reported by Sullivan et al. who reported on a heterozygous missense Glu847Lys (E847K) mutation in the HK1 gene that segregated fully with the disease in each family (Citation9). None of the patients had any extraocular manifestations, and none had any systemic abnormalities in glycolysis (Citation9). Later, several groups reported similar non-syndromic autosomal dominant retinitis pigmentosa or allied diseases with the same heterozygous E847K mutation in the HK1 gene (Citation10–13). Most recently, seven patients from six unrelated families with NEDVIBA were reported by Okur et al. They identified four different de novo heterozygous missense mutations in the HK1 gene in these patients (Citation14). They also reported that these patients were syndromic, and several cases had a combination of retinitis pigmentosa and optic atrophy. However, the inheritance pattern and detailed ophthalmic findings were uncertain because a pedigree analysis and fundus images were not presented (Citation14).
The purpose of this study was to determine the phenotypic characteristics of the members of a Japanese family with a recurrent E847K mutation in the HK1 gene. To accomplish this, the family members underwent comprehensive ocular examinations including high-resolution retinal imaging by an adaptive optics fundus camera.
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