Mutant GlialCAM Causes Megalencephalic Leukoencephalopathy with Subcortical Cysts, Benign Familial Macrocephaly, and Macrocephaly with Retardation and Autism

Abstract

Megalencephalic leukoencephalopathy with subcortical cysts (MLC) is a leukodystrophy characterized by early-onset macrocephaly and delayed-onset neurological deterioration. Recessive MLC1 mutations are observed in 75% of patients with MLC. Genetic-linkage studies failed to identify another gene. We recently showed that some patients without MLC1 mutations display the classical phenotype; others improve or become normal but retain macrocephaly. To find another MLC-related gene, we used quantitative proteomic analysis of affinity-purified MLC1 as an alternative approach and found that GlialCAM, an IgG-like cell adhesion molecule that is also called HepaCAM and is encoded by HEPACAM, is a direct MLC1-binding partner. Analysis of 40 MLC patients without MLC1 mutations revealed multiple different HEPACAM mutations. Ten patients with the classical, deteriorating phenotype had two mutations, and 18 patients with the improving phenotype had one mutation. Most parents with a single mutation had macrocephaly, indicating dominant inheritance. In some families with dominant HEPACAM mutations, the clinical picture and magnetic resonance imaging normalized, indicating that HEPACAM mutations can cause benign familial macrocephaly. In other families with dominant HEPACAM mutations, patients had macrocephaly and mental retardation with or without autism. Further experiments demonstrated that GlialCAM and MLC1 both localize in axons and colocalize in junctions between astrocytes. GlialCAM is additionally located in myelin. Mutant GlialCAM disrupts the localization of MLC1-GlialCAM complexes in astrocytic junctions in a manner reflecting the mode of inheritance. In conclusion, GlialCAM is required for proper localization of MLC1. HEPACAM is the second gene found to be mutated in MLC. Dominant HEPACAM mutations can cause either macrocephaly and mental retardation with or without autism or benign familial macrocephaly.

Megalencephalic leukoencephalopathy with cysts: theGlialcam‐null mouse model

“…Recessive mutations in MLC1 and GLIALCAM lead to loss of MLC1 function causing indistinguishable clinical phenotype and brain MRI abnormalities in patients 12, 14. In agreement with this, Glialcam ‐null and Mlc1 ‐null mice show largely overlapping neuropathology.…”

“…MLC is caused by mutations in the MLC1 or GLIALCAM gene 11, 12. GlialCAM is a protein chaperone ensuring the correct membrane localization of MLC1 13.…”

“…Recessive mutations in both genes cause loss of MLC1 function and an indistinguishable clinical phenotype 12, 14. Dominant, heterozygous GLIALCAM mutations initially lead to the same disease, but improvement occurs afterward and the white matter abnormalities largely disappear 12, 14…”

Seizures and disturbed brain potassium dynamics in the leukodystrophy megalencephalic leukoencephalopathy with subcortical cysts

“…“Megalencephalic leukoencephalopathy with subcortical cysts” (MLC; MIM 604004) is a rare childhood‐onset leukodystrophy,1, 2 caused by homozygous recessive mutations in MLC1 3 or GLIALCAM 4. MLC1 is a membrane protein almost exclusively expressed in brain astrocytes 5.…”

“…MLC1 is a membrane protein almost exclusively expressed in brain astrocytes 5. GlialCAM is a chaperone of MLC1, ensuring its localization in the membrane of astrocyte endfeet 4, 6, 7. Patients show very high water content in the brain white matter.…”