De novo variants in HK1 associated with neurodevelopmental abnormalities and visual impairment

Abstract

Hexokinase 1 (HK1) phosphorylates glucose to glucose-6-phosphate, the first rate-limiting step in glycolysis. Homozygous and heterozygous variants in HK1 have been shown to cause autosomal recessive non-spherocytic hemolytic anemia, autosomal recessive Russe type hereditary motor and sensory neuropathy, and autosomal dominant retinitis pigmentosa (adRP). We report seven patients from six unrelated families with a neurodevelopmental disorder associated with developmental delay, intellectual disability, structural brain abnormality, and visual impairments in whom we identified four novel, de novo missense variants in the N-terminal half of HK1. Hexokinase activity in red blood cells of two patients was normal, suggesting that the disease mechanism is not due to loss of hexokinase enzymatic activity.

High-resolution photoreceptor imaging analysis of patients with autosomal dominant retinitis pigmentosa (adRP) caused by HK1 mutation

“…None of the patients with the E847K mutation had optic disc atrophy. There is also a report describing patients with syndromic RP and/or optic atrophy caused by Gly414Glu, Ser445Leu, and Thr457Met mutations in the HK1 gene (14). From these earlier findings and our data, we conclude that patients Figures 8E and 8 F. Cone density of patient II-3 are not countable throughout 2 to 5 degrees.…”

“…Later, several groups reported similar non-syndromic autosomal dominant retinitis pigmentosa or allied diseases with the same heterozygous E847K mutation in the HK1 gene (10)(11)(12)(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 (14). They also reported that these patients were syndromic, and several cases had a combination of retinitis pigmentosa and optic atrophy.…”

“…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 (14).…”

A pig BodyMap transcriptome reveals diverse tissue physiologies and evolutionary dynamics of transcription

“…12c ) that were critical specifiers for different germ layers. For example, neurodevelopmental genes (such as HK1 28 , VWC2 29 , and NECTIN1 30 ) , a metabolic gene (FOXA3) 31 , and genes in involved in cardiovascular differentiation ( TMEM88 32 and VIM 33 ) were highly expressed in tissues derived from ectoderm (i.e., cerebrum, cerebellum, and retina), endoderm (i.e., liver, small intestine, colon, and stomach), and mesoderm (typically, heart), respectively (Supplementary Fig. 12d ).…”

A novel remitting leukodystrophy associated with a variant in FBP2

“…However, heterozygous de novo missense mutations in the same gene detected recently in six patients with developmental delay, intellectual disability, structural brain abnormality and visual impairment, were associated with normal hexokinase activity. 31 …”