Alternative titles; symbols
HGNC Approved Gene Symbol: MLC1
Cytogenetic location: 22q13.33 Genomic coordinates (GRCh38): 22:50,059,391-50,085,875 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 22q13.33 | Megalencephalic leukoencephalopathy with subcortical cysts 1 | 604004 | Autosomal recessive | 3 |
MLC1 encodes a transmembrane protein that associates with the Na,K-ATPase beta-1 subunit (ATP1B1; 182330) in a multiprotein complex. MLC1 regulates the assembly and response of this Na,K-ATPase complex to osmotic stress (Lanciotti et al., 2012).
Nomura et al. (1994) identified MLC1, which they designated KIAA0027, by analysis of randomly sampled cDNA clones from a human immature myeloid cell line. Northern blot analysis showed that expression of KIAA0027 was relatively high in brain. It was also expressed in peripheral white blood cells and spleen, with relatively low expression in ovary, prostate, placenta, thymus, and lung. No expression was observed in heart, liver, skeletal muscle, and several other tissues.
Leegwater et al. (2001) confirmed that MLC1 is expressed in brain, and they did not detect alternative splice products. MLC1 was predicted to have 8 transmembrane domains. Leegwater et al. (2001) hypothesized that MLC1 encodes a membrane protein that may have a transport function for a specific substrate.
Teijido et al. (2004) showed that human MLC1 localized to the plasma membrane in Xenopus oocytes. Mouse Mlc1 showed similar localization in HeLa cells. MLC1 was found to be an oligomeric protein. In adult mouse brain, Mlc1 was detected preferentially in particular axonal tracts and in some astrocytes, concentrating in Bergmann glia, the astrocyte end-feet membranes adjacent to blood vessels, and in astrocyte-astrocyte membrane contact regions, as well as the ependyma and the pia mater.
Lanciotti et al. (2012) stated that the MLC1 protein contains 377 amino acids.
Leegwater et al. (2001) determined that the MLC1 gene contains 12 exons with a start codon in exon 2 and an untranslated 3-prime end of 2.2 kb.
By radiation hybrid analysis, Nomura et al. (1994) mapped the MLC1 gene, or KIAA0027, to chromosome 22. Durand et al. (2007) mapped the MLC1 gene to chromosome 22q13.33 by study of a translocation, t(14;22)(p11.2;q13.33).
By quantitative proteomic analysis of affinity-purified MLC1, Lopez-Hernandez et al. (2011) identified HEPACAM (611642) as a direct MLC1-binding partner. Immunohistochemistry of human brain tissue showed HEPACAM expression mainly around blood vessels. Double immunostaining with a monoclonal antibody against HEPACAM and a polyclonal antibody against human MLC1 showed that MLC1 and HEPACAM colocalized at astrocytic end-feet in astrocyte-astrocyte junctions. The HEPACAM protein was localized inside axons, in contact regions between myelin and axons, and in cells that surrounded myelin.
Lopez-Hernandez et al. (2011) found no changes in endogenous HEPACAM protein in primary astrocyte culture that had been depleted of MLC1 by RNA interference: HEPACAM was detected in astrocyte-astrocyte processes in MLC1-depleted astrocytes. The studies suggested that HEPACAM subcellular localization is independent of MLC1 expression. Additional in vitro studies showed that both HEPACAM and MLC1 homooligomerize, as well as heterooligomerize with each other. When coexpressed, both proteins were localized in astrocyte-astrocyte cell junctions. However, MLC1 expressed alone was detected at the plasma membrane, but was not particularly enriched in cell junctions. In contrast, HEPACAM expressed alone was clearly detected in cell junctions. The findings indicated that HEPACAM acts as an escort molecule, necessary to bring MLC1 to cell-cell junctions.
Using various methods, Lanciotti et al. (2012) found that MLC1 interacted directly with ATP1B1 as part of an Na,K-ATPase multiprotein complex that mediated swelling-induced cytosolic calcium increase and volume recovery in response to hyposmosis in rat and human astrocyte cell lines. Other components of this complex included the potassium channel Kir4.1 (KCNJ10; 602208), syntrophin (see 601017), caveolin-1 (CAV1; 601047), HEPACAM, and the calcium channel TRPV4 (605427). AQP4 (600308) was recruited to the complex following hyposmotic shock. Association of MLC1 with ATPB1 was favored by hyposmotic shock. Membrane expression of MLC1 potentiated complex assembly and agonist- or hyposmotic shock-induced TRPV4 activation and calcium influx.
Leegwater et al. (2001) identified 12 different mutations in the MLC1 gene (see, e.g., 605908.0001-605908.0004) in individuals with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004) in 13 separate families, 7 of which were informative for linkage to 22qtel. The patients in 1 family were compound heterozygotes for mutations that introduced stop codons. The others were homozygous for frameshifts, splice acceptor mutations, a splice donor mutation, and amino acid substitutions of residues in predicted transmembrane domains.
Leegwater et al. (2002) described 14 new mutations in the MLC1 gene (see, e.g., 605908.0005-605908.0008) in 18 patients with MLC. They found no MLC1 mutations in 14 families; however, 4 of these families were informative for linkage, and 3 families did not display linkage to 22qter, which strongly suggested the presence of a second locus.
In Israel, MLC is found in an increased frequency among Libyan Jews. Ben-Zeev et al. (2002) described 3 novel mutations in affected members of 7 MLC families: gly59 to glu (G59E; 605908.0009), pro92 to ser (P92S; 605908.0007), and 135insC (605908.0011). The G59E mutation was found in a great majority of MLC patients in Israel. Screening of 200 normal Libyan Jewish individuals for the mutation revealed a carrier rate of 1 in 40 compared with an expected carrier rate of 1 in 81. Several explanations were offered for this observation, the most likely one being an admixture of the Libyan Jewish population reducing the number of homozygotes.
In 13 of 18 patients with MLC, Patrono et al. (2003) identified 11 mutations in the MLC1 gene, 9 of which were novel. There was no apparent genotype/phenotype correlation. Five patients did not show mutations, indicating genetic heterogeneity.
Tsujino et al. (2003) studied 3 Japanese patients with megalencephalic leukoencephalopathy, also known as van der Knaap disease. Two of them were homozygous for a previously described mutation, S93L (605908.0002), and 1 was a compound heterozygote for S93L and a novel mutation (605908.0012). Combining their data with previous reports, they determined that S93L had been observed in 6 of 7 (85.7%) patients in at least 1 allele, and 10 of 14 (71.4%) alleles had this mutation.
Ilja Boor et al. (2006) demonstrated that in about 20% of patients with a typical clinical and MRI picture of megalencephalic leukoencephalopathy with subcortical cysts, no mutations in the MLC1 gene had been found. Several of these families in which no mutations had been found also do not show linkage with the MLC1 locus, which suggested 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 or 3-prime and 5-prime untranslated regions, and intronic mutations, which may influence the amino acid composition of the end product. Ilja Boor et al. (2006) described 13 novel mutations, including those found with extended mutation analysis on MLC patients.
Functional Effects of MLC1 Mutations
Teijido et al. (2004) found that mutant MLC1 had decreased expression and reduced stability compared to wildtype MLC1, suggesting that mutant MLC1 impaired folding. The defect was corrected in vitro by addition of curcumin, a Ca(2+)-ATPase inhibitor. Duarri et al. (2008) demonstrated that disease-causing mutations in MLC1 resulted in a reduction of total MLC1 protein and decreased expression at the plasma membrane in human monocytes, Xenopus oocytes, and rat astrocytes. In vitro analysis in several cell lines showed that the MLC1-mutant proteins had decreased stability, were retained in the endoplasmic reticulum, and were subject to proteosomal or lysosomal degradation, consistent with a defect in protein trafficking. Mutations were classified based on reduction of MLC1 protein levels in plasma membranes as severe (see, e.g., S280L, 605908.0001; S93L, 605908.0002; and N141S, 605908.0006), intermediate (see, e.g., G59E, 605908.0009; P92S, 605908.0007), or mild (see, e.g., N141K; 605908.0006). Duarri et al. (2008) suggested increasing the cellular expression or stability of MLC1 as a therapeutic approach for patients with MLC1 mutations.
Lanciotti et al. (2012) found that mutations in MLC1 hindered the response of rat and human astrocytes to hyposmotic stress. Mutations in MLC1 associated with a severe phenotype, including S280L, resulted in absence of MLC1 at the membrane and abrogated assembly of the Na,K-ATPase complex and TRPV4-mediated calcium influx in response to hyposmotic stress. Mutations associated with a less severe phenotype had a milder effect on Na,K-ATPase complex assembly and the response to hyposmotic stress.
By immunohistochemical analysis, Sirisi et al. (2014) observed mislocalization of GLIALCAM (HEPACAM; 611642) in Bergmann glia in the cerebellum of the patient with megalencephalic leukoencephalopathy with subcortical cysts-1 reported by Lopez-Hernandez et al. (2011).
Exclusion Studies
Meyer et al. (2001) suggested that KIAA0027/MLC1 is involved in the etiopathogenesis of schizophrenia (181500), via a putative dominantly acting rare leu309-to-met (L309M) variant cosegregating in a large pedigree with periodic catatonia. A form of periodic catatonia had been mapped to chromosome 15q15 (SCZD10; 605419). McQuillin et al. (2002) screened exon 11 of the MLC1 gene in 174 U.K. patients with schizophrenia, including 22 cases of catatonic schizophrenia, and did not identify any individual with the L309M mutation. They did, however, identify a series of polymorphisms, including an insertion of 11 amino acids at amino acids 351 to 352, which were in complete linkage disequilibrium with each other and which were present in an equal number of schizophrenic and control individuals. McQuillin et al. (2002) concluded that the identification of these polymorphisms in healthy individuals suggests that MLC1 exon 11 can withstand a number of changes without producing either the MLC phenotype or schizophrenia. Rubie et al. (2003) screened the MLC1 gene in 140 index cases with periodic catatonia and 5 patients with MLC. The rare L309M variant was found in another multiplex pedigree but did not segregate with periodic catatonia. Furthermore, a complicated 33-bp insertion/deletion polymorphism at the 5-prime end of exon 11 of MLC1 was found at equal frequency among schizophrenic patients and controls. Among the 5 patients with MLC, 4 mutant alleles were detected. Rubie et al. (2003) concluded that their findings excluded MLC1 as a susceptibility locus for schizophrenia.
Sirisi et al. (2014) found that the zebrafish genome contains 2 GLIALCAM (HEPACAM; 611642) paralogs, glialcama and glialcamb, of which only glialcama exhibited subcellular localization and modulation of the chloride channel Clc2 (CLCN2; 600570) similar to that of mammalian GLIALCAM. Similar to findings in mouse, mlc1 and glialcama colocalized in zebrafish glial cells, especially around brain barriers, radial glia processes and endfeet, and in retinal Muller glia. Mlc1 -/- zebrafish showed minor lesions and megalencephaly in brain, but not myelin vacuolization. However, absence of mlc1 in zebrafish brain, as in mice, led to mislocalization of glialcama. Glialcama mislocalization was not found in cultured Mlc1 -/- mouse astrocytes unless they were exposed to high extracellular potassium, a condition that mimicked neuronal activity.
In a Japanese family with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004), Leegwater et al. (2001) identified a homozygous C-to-T transition at nucleotide 954 in exon 10 of the MLC1 gene, resulting in a ser280-to-leu substitution.
In a Japanese family and a Turkish family, Leegwater et al. (2001) identified a homozygous C-to-T transition at nucleotide 393 in exon 4 of the MLC1 gene, resulting in a ser93-to-leu (S93L) substitution and causing megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004). In another Japanese family, the S93L mutation was found in heterozygous state in an affected individual.
Tsujino et al. (2003) assembled data indicating that of 7 Japanese patients, 6 (85.7%) carried the S93L mutation on at least 1 allele and 10 of the 14 alleles (71.4%) had this mutation.
In 2 families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), one from Turkey and the other from the Middle East, Leegwater et al. (2001) identified a 7-bp deletion in exon 6 of the MLC1 gene, resulting in a frameshift after leu149.
In a family of Turkish origin with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Leegwater et al. (2001) identified a homozygous donor splice site mutation causing aberrant splicing of exon 11 of the MLC1 gene.
In a family in France, Leegwater et al. (2002) found megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004) caused by homozygosity for an asn141-to-lys (N141K) missense mutation in exon 5 of the MLC1 gene. The amino acid change resulted from a C-to-A transversion at nucleotide 423.
In a family in Turkey, Leegwater et al. (2002) found that homozygosity for an asn141-to-ser (N141S) missense mutation in exon 5 of the MLC1 gene was responsible for megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004). The amino acid change resulted from an A-to-G transition at nucleotide 422.
In 3 unrelated families with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), 2 from Croatia and 1 from U.K./Eastern Europe, Leegwater et al. (2002) found compound heterozygosity for mutations in the MLC1 gene, with 1 of the alleles carrying a pro92-to-ser (P92S) missense mutation. The amino acid change resulted from a C-to-T transition at nucleotide 274. In the U.K./Eastern Europe case, the second mutation was tyr198-to-ter (605908.0008), described by Leegwater et al. (2001).
In a family of mixed Jewish ancestry (the father a Libyan Jew and the mother an Ashkenazi Jew) with megalencephalic leukoencephalopathy with subcortical cysts, Ben-Zeev et al. (2002) identified the P92S substitution. The mutation was not found in 140 unaffected Ashkenazi control chromosomes.
For discussion of the tyr198-to-ter mutation in the MLC1 gene that was found in compound heterozygous state in a U.K./Eastern Europe patient with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004) by Leegwater et al. (2001, 2002), see 605908.0007.
Ben-Zeev et al. (2002) showed that Libyan Jewish patients with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004) were homozygous for a G-to-A substitution at nucleotide 176 of the MLC1 gene, resulting in a gly59-to-glu (G59E) change. This sequence variation was found in full segregation with the disease in all of the Libyan Jewish and Turkish Jewish families studied, and in the carrier chromosome inherited from a Libyan Jewish father in a mixed Ashkenazi-Libyan Jewish family. This substitution was not found in 200 unaffected, non-Libyan Jewish individuals, but was found in 5 of 200 unaffected Libyan Jewish individuals, establishing a carrier rate of 1 in 40 in this ethnic group.
In a patient of Indian Agrawali ancestry with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Ben-Zeev et al. (2002) identified a homozygous insertion of a cytosine at nucleotide 135 at exon 2 of the MLC1 gene. This resulted in a frameshift and the creation of a stop codon 104 bp downstream.
Leegwater et al. (2002) described this mutation in 3 Agrawali patients. They stated that the disease was probably introduced into the tribe by a single founder, and the mutation is probably shared by all MLC patients of this community.
In a patient with megalencephalic leukoencephalopathy with subcortical cysts (MLC1; 604004), Tsujino et al. (2003) described compound heterozygosity for the common S93L mutation (605908.0002) and a novel mutation, 452-468del+G.
In a woman with megalencephalic leukoencephalopathy with subcortical cysts-1 (MLC1; 604004), Lopez-Hernandez et al. (2011) identified a homozygous 206C-T transition in the MLC1 gene, resulting in a ser69-to-leu (S69L) substitution in a highly conserved residue in the first transmembrane domain. The mutation was not found in 400 control chromosomes. The patient developed macrocephaly within the first few months of life, and thereafter showed slow motor deterioration, epilepsy, and cognitive decline. Brain MRI at age 40 years showed diffuse signal abnormalities in the cerebral white matter, with global atrophy and subcortical cysts in the anterior temporal region. She died at age 57 years following a cranial trauma. Postmortem brain examination showed reduced cerebral white matter with cavitation in the frontal and parietal lobes. Microscopic examination showed preservation of the cerebral cortex, but lack of myelin in the deep white matter with cavitation in the most affected areas. There was a reduction in the number of astrocytes and oligodendrocytes and loss of axons. Many astrocytes lacking myelin contained alpha-beta-crystallin (CRYAB; 123590), a stress protein. Patient tissue showed no immunostaining for MLC1, indicating that deficiency of cell surface MLC1 protein expression is the basis for the disorder. The MLC1-interacting protein HEPACAM (611642) was present in astrocytic processes, but at a reduced level. In vitro expression of the S69L mutation in HeLa cells showed that the mutant protein was located in intracellular compartments, with reduced surface membrane expression compared to wildtype. The mutant protein also showed reduced stability. The mutant protein was stabilized by overexpression of HEPACAM, but it was still less stable than wildtype.
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