9.B.129. The Membrane Protein MLC1 (MLC1) Family Defects in MLC1 are a cause of leukoencephalopathy megalencephalic with subcortical cysts type 1 (MLC1). MLC1 is a syndrome of cerebral leukoencephalopathy and megalencephaly characterized by ataxia, spasticity, seizures, delay in motor development and mild mental retardation. The brain appears swollen on magnetic resonance imaging, with diffuse white-matter abnormalities and the invariable presence of subcortical cysts in frontal and temporal lobes. MLC1 interacts structurally and functionally with several ion/water channels and transporters and ion channel accessory proteins (Brignone et al. 2015). MLC1 mutations cause MLC1and brain channelopathies.
References:
Boor, P.K., K. de Groot, Q. Waisfisz, W. Kamphorst, C.B. Oudejans, J.M. Powers, J.C. Pronk, G.C. Scheper, and M.S. van der Knaap. (2005). MLC1: a novel protein in distal astroglial processes. J Neuropathol Exp Neurol 64: 412-419.
Brignone, M.S., A. Lanciotti, S. Camerini, C. De Nuccio, T.C. Petrucci, S. Visentin, and E. Ambrosini. (2015). MLC1 protein: a likely link between leukodystrophies and brain channelopathies. Front Cell Neurosci 9: 66.
Dubey, M., E. Brouwers, E.M.C. Hamilton, O. Stiedl, M. Bugiani, H. Koch, M.H.P. Kole, U. Boschert, R.C. Wykes, H.D. Mansvelder, M.S. van der Knaap, and R. Min. (2018). Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts. Ann Neurol 83: 636-649.
Nicolson, G.L. and G. Ferreira de Mattos. (2022). Fifty Years of the Fluid-Mosaic Model of Biomembrane Structure and Organization and Its Importance in Biomedicine with Particular Emphasis on Membrane Lipid Replacement. Biomedicines 10:.
Pérez-Rius, C., M. Folgueira, X. Elorza-Vidal, A. Alia, M.B. Hoegg-Beiler, M.N.H. Eeza, M.L. Díaz, V. Nunes, A. Barrallo-Gimeno, and R. Estévez. (2019). Comparison of zebrafish and mice knockouts for Megalencephalic Leukoencephalopathy proteins indicates that GlialCAM/MLC1 forms a functional unit. Orphanet J Rare Dis 14: 268.
Sirisi, S., X. Elorza-Vidal, T. Arnedo, M. Armand-Ugón, G. Callejo, X. Capdevila-Nortes, T. López-Hernández, U. Schulte, A. Barrallo-Gimeno, V. Nunes, X. Gasull, and R. Estévez. (2017). Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes: implications in megalencephalic leukoencephalopathy. Hum Mol Genet 26: 2436-2450.
Examples:
TC#	Name	Organismal Type	Example
9.B.129.1.1	Megalencephalic leukoencephalopathy with subcortical cysts 1 homologue, MLC1. May interact with several ion and water channels and cause channelopathies (Brignone et al. 2015). The disease is a progressive cerebral white matter disease in children caused by mutations in the MLC1 gene. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC1 is mainly expressed in the brain and leukocytes. MLC1 contains an even number (probably 8) TMSs and is expressed in distal astroglial processes in perivascular, subependymal, and subpial regions, possibly suggesting a role in transport across the blood-brain and brain-cerebrospinal fluid barriers. Astrocytes are of fundamental importance in maintaining the structural and functional integrity of neural tissue (Boor et al. 2005). GlialCAM/MLC1 may form a functional unit (Pérez-Rius et al. 2019). Disturbed astrocyte regulation of ion and water homeostasis in MLC causes hyperexcitability of neuronal networks and seizures, suggesting a role for astrocytes in volume regulation in epilepsy (Dubey et al. 2018). Depolarization causes the formation of a ternary complex between GlialCAM, MLC1 and ClC-2 in astrocytes (Sirisi et al. 2017). MLC1 depends on the fluid mosaic membrane which has been reviewed (Nicolson and Ferreira de Mattos 2022).	Animals	*MLC1 of Homo sapiens* (Q15049)**

9.B.129.1.2	MLC1 homolog of 414 aas and 6 or 7 TMSs.		MLC1 homolog of Liparis tanakae

9.B.129.1.3	Uncharacterized protein of 310 aas and 5 or 6 TMSs in a 1 or 2 + 4 TMS arrangement.		UP of Cyprinus carpio

9.B.129.1.4	Uncharaacterized protein of 307 aas and 6 TMSs.		UP of Takifugu flavidus