Category: Research

Month: 25 Nov 2014

Issue: not yet available

Newly discovered mutation may account for up to 1% of autosomal dominant retinitis pigmentosa (RP)

Collaborative research, led by the Human Genetics Centre at the University of Texas Health Science Centre in Houston, has successfully described a new genetic mutation in a novel disease gene on chromosome 10q22.1. Exomic sequencing in a large six-generation family led to the identification of a novel coding variant in the hexokinase 1 (HK1) gene. The variant was found in all affected individuals but was absent among normal controls. Hexokinase 1 is known to catalyze phosphorylation of glucose to glucose-6-phosphate however, no systemic abnormalities were detected in individuals carrying the variant suggesting the mutation may only impact on the retina.

 

Retinitis pigmentosa is an extremely heterogeneous disorder at both the genetic and clinical levels, sometimes with varying phenotypes within families harbouring the same genetic etiology. In non-syndromic RP there are over 70 genes identified – mutations in 24 genes are known to cause autosomal dominant RP, 45 genes are involved in recessive RP while 3 genes are known to cause X-linked RP. There is no single functional category into which all these genes fit, instead they encompass a variety of physiological activities including phototransduction, pre-mRNA processing, ciliary proteins, structural proteins and many more. Linkage analysis among affected family members highlighted a 9Mb region on chromosome 10q21.3-10q22.1, comprising 96 putative genes of which 87 coded for a gene product. Exome sequencing uncovered a single non-polymorphic coding variant, HK1 p.Gly847Lys, among all affected family members and absent from normal controls.

 

A review of the clinical records of affected individuals showed considerable variability with some individuals reporting night blindness from early childhood while others did not appear to show any symptoms until the 5th or 6th decade of life. A key question is how this mutation in the HK1 gene causes retinal dystrophy. The HK1 protein catalyzes the first step in glycolysis, where glucose is converted to G6P where it can be metabolized within cells. However, the p.Gly847Lys mutation is not near the active site of the enzyme and so it is unlikely that perturbation of glycolysis is at the root of the problem. Notwithstanding such, the p.Gly847Lys mutation occurs at a highly conserved site across all vertebrate HK1s – the glutamic acid at position 847 is 100% conserved in the 100 HK1 vertebrate genes that have been sequenced to date. As such, the moiety is likely to have some other critical function however, despite considerable research, the region has not been implicated in any enzymatic function. Concluding their report the research team comment that, “The location of the amino acid substitution in HK1 is far from any mapped functional site, and there is no indication that enzymatic activity is impaired. Thus the HK1 adRP mutation may act through a unique biological mechanism”.

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