Conservation of the glucan phosphatase laforin is linked to rates of molecular evolution and the glucan metabolism of the organism

Matthew S Gentry,Rachel M Pace

doi:10.1186/1471-2148-9-138

Matthew S Gentry, Rachel M Pace

Open Access

https://doi.org/10.1186/1471-2148-9-138

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Journal: BMC Evolutionary Biology	Publication Date: Jan 1, 2009
Citations: 108	License type: cc-by

Affiliation: University of Kentucky

Abstract

BackgroundLafora disease (LD) is a fatal autosomal recessive neurodegenerative disease. A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Mutations in the gene encoding the phosphatase laforin account for ~50% of LD cases, and this gene is conserved in all vertebrates. We recently demonstrated that laforin is the founding member of a unique class of phosphatases that dephosphorylate glucans.ResultsHerein, we identify laforin orthologs in a protist and two invertebrate genomes, and report that laforin is absent in the vast majority of protozoan genomes and it is lacking in all other invertebrate genomes sequenced to date. We biochemically characterized recombinant proteins from the sea anemone Nematostella vectensis and the amphioxus Branchiostoma floridae to demonstrate that they are laforin orthologs. We demonstrate that the laforin gene has a unique evolutionary lineage; it is conserved in all vertebrates, a subclass of protists that metabolize insoluble glucans resembling LBs, and two invertebrates. We analyzed the intron-exon boundaries of the laforin genes in each organism and determine, based on recently published reports describing rates of molecular evolution in Branchiostoma and Nematostella, that the conservation of laforin is linked to the molecular rate of evolution and the glucan metabolism of an organism.ConclusionOur results alter the existing view of glucan phosphorylation/dephosphorylation and strongly suggest that glucan phosphorylation is a multi-Kingdom regulatory mechanism, encompassing at least some invertebrates. These results establish boundaries concerning which organisms contain laforin. Laforin is conserved in all vertebrates, it has been lost in the vast majority of lower organisms, and yet it is an ancient gene that is conserved in a subset of protists and invertebrates that have undergone slower rates of molecular evolution and/or metabolize a carbohydrate similar to LBs. Thus, the laforin gene holds a unique place in evolutionary biology and has yielded insights into glucan metabolism and the molecular etiology of Lafora disease.

Highlights

Lafora disease (LD) is a fatal autosomal recessive neurodegenerative disease
Carbohydrate binding modules (CBMs) are domains typically found in glucosylhydrolases and glucotransferases in bacterial, fungal, or plant genomes [25,26,27]
Laforin and starch excess 4 (SEX4) have evolutionarily distinct CBMs, multiple groups have proposed that carbohydrate binding module-family 20 (CBM20) and carbohydrate binding module-family 21 (CBM21) may share a common evolutionary origin and suggest keeping distinct families grouped into a common CBM clan [28,29,30,31]

Summary

Introduction

A hallmark of LD is cytoplasmic accumulation of insoluble glucans, called Lafora bodies (LBs). Lafora disease (LD; OMIM 254780) is an autosomal recessive neurodegenerative disorder. It is one of five major progressive myoclonus epilepsies (PMEs) [1]. BMC Evolutionary Biology 2009, 9:138 http://www.biomedcentral.com/1471-2148/9/138 among the PMEs because of the patient's rapid neurological deterioration and the accumulation of insoluble glucans/carbohydrates called Lafora bodies (LB) [5,6]. Number of seizures, and LB accumulation as they age; it is hypothesized that LBs trigger these symptoms and the death of the patient [6]. LD patients exhibit increased neuronal cell death, EPM2A (epilepsy of progressive myoclonus type 2) is mutated in ~50% LD cases [9,10].

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