L LAD ▶ SH2D2A Laforin: Function and Action of a Glucan Phosphatase Amanda R. Sherwood, Vikas V. Dukhande and Matthew S. Gentry Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, KY, USA Synonyms EPM2A; LAF-PTPase; MELF Historical Background Two groups searching for genes mutated in Lafora disease patients simultaneously discovered the EPM2A gene (epilepsy, progressive myoclonic type 2A) that encodes the protein laforin (Minassian et al. 1998; Serratosa et al. 1995). Laforin is a bimodular protein containing a dual specificity phosphatase (DSP) domain and a carbohydrate-binding module (CBM) (Fig. 1). Dual specificity phosphatases (DSPs) are a diverse group of phosphatases whose mem- bers dephosphorylate phosphoserine/phosphothreonine, phosphotyrosine, phosphoinositols, ribo/deoxyribonu- cleotide 5 0 -triphosphates, pyrophosphate/triphosphate, or phospho-glucans. DSPs are members of the larger protein tyrosine phosphatase (PTP) superfamily that all utilize a cysteine-dependent mechanism to hydrolyze phosphoester bonds. This mechanism is dependent on the conserved CX 5 R active site motif common to all protein tyrosine phosphatases. Laforin is the founding member of a small group within the DSPs called the glucan phosphatases, that is, laforin liberates phos- phate from glucans such as glycogen. CBMs are divided into 63 families based on primary, secondary, and, when available, tertiary structure. In addition to binding and dephosphorylating glucans, laforin also appears to act as a scaffolding protein. The gene encoding laforin is conserved in all vertebrates and in a subset of protists and invertebrates (Gentry et al. 2007). Loss of function recessive mutations in the gene encoding laforin results in a fatal disease called Lafora disease (LD). Lafora Disease Lafora disease (LD) is a fatal neurodegenerative epi- lepsy that is autosomal recessive and is characterized by declining neurological functions over time. LD is one of four diseases that represent the inherited pro- gressive myoclonus epilepsy (PME) family; the PMEs collectively constitute  1% of all epilepsies. Due to the progressive nature of neurodegeneration, the frequency of myoclonic seizures, and the variety of seizure types that can present, PMEs are often difficult to diagnose at onset (reviewed in Minassian 2001). Lafora disease is characterized by myoclonic, tonic-clonic, and focal-occipital seizures among other S. Choi (ed.), Encyclopedia of Signalling Molecules, DOI 10.1007/978-1-4419-0461-4, # Springer Science+Business Media, LLC 2012