Megalencephalic leukoencephalopathy with subcortical cysts: an update and extended mutation analysis ofMLC1

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is an autosomal recessive cerebral white matter disorder in children. This disease is histopathologically characterized by myelin splitting and intramyelinic vacuole formation. MLC is caused by mutations in the gene MLC1, which encodes a novel protein, MLC1. Since the first report, 50 mutations in this gene have been found. Mutations occur throughout the entire coding region and include all different types: 11 splice-site mutations; one nonsense mutation; 24 missense mutations; and 14 deletions and insertions. Until now, six polymorphisms within the coding sequence of MLC1 had been reported. In about 20% of the patients with a typical clinical and MRI picture, no mutations in the MLC1 gene are found. Several of the families, in which no mutations are found, also do not show linkage with the MLC1 locus, which suggests a second gene involved in MLC. The absence of mutations may also be the consequence of performing standard mutation analysis that can miss heterozygous deletions, mutations in the promoter, 3' and 5' untranslated regions (UTRs), and intron mutations, which may influence the amino acid composition of the end product. In this work we describe 13 novel mutations, including those found with extended mutation analysis on MLC patients. This study shows that extended mutation analysis is a valuable tool to identify at least some of the missing mutations. Therefore, we suggest extended mutation analysis for the MLC1 gene, if no mutations are found during standard analysis.

Functional Studies of MLC1 Mutations in Chinese Patients with Megalencephalic Leukoencephalopathy with Subcortical Cysts

“…Another research showed that mutation C326R reduced MLC1 mRNA expression [20]. Further, decline of MLC1 protein and mRNA expression had also been found in monocytes from MLC patients [31].…”

“…Until now, there are around 70 MLC-related mutations of MLC1 have been reported in patients of various ethnic backgrounds (human gene mutation database, HGMD). Despite this, families without identifiable mutation at the MLC1 locus had been found [3], [20], and the existence of at least one other locus had been suggested before [21], [22]. Recently, López-Hernández T et al found mutations in GlialCAM encoded by HEPACAM in some MLC patients without MLC1 mutations.…”

Adult Spinal Cord Radial Glia Display a Unique Progenitor Phenotype

“…Of the core nine genes shared in all three progenitor niches, some are known NSC regulatory genes ( Sox2 , Ascl1 , Lxn , Id4 ), whereas others ( Mlc1 , Gja1 , Cd63 ) are human disease genes that now represent candidate regulatory pathways that serve a common role in regulating different CNS progenitors. Of these, Mlc1 deserves particular attention for its potential function in postnatal progenitors, as mutations in Mlc1 lead to the chronic demyelinating disorder Megalencephalic leukoencephalopathy with Subcortical Cysts- a disease that features an over-production of neural cells early during the first year of life that results in a paucity of myelin and macrocephaly [27]. Although Mlc1 function is uncharacterized, its enrichment in all three NSC niches suggests a regulatory role in postnatal progenitor proliferation.…”

Selective expression of eGFP in mouse perivascular astrocytes by modification of the Mlc1 gene using T2A‐based ribosome skipping

“…Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a heritable human disease associated with loss-of-function mutations in the MLC1 gene (Ilja Boor et al ., 2006; Leegwater et al ., 2001; van der Knaap et al ., 1995). Mlc1 is a 38-kDa domain protein and shares sequence homology with K + ion channels (Boor et al ., 2005).…”