Dysfunctional ADAM22 implicated in progressive encephalopathy with cortical atrophy and epilepsy
Mikko Muona1, Yuko Fukata1, Anna-Kaisa Anttonen1
1Institute for Molecular Medicine Finland (M.M., A.P.), Neuroscience Center (M.M., A.L., A.-E.L.), and Research Programs Unit, Molecular Neurology (M.M., A.-K.A., A.L., A.-E.L.), University of Helsinki, Finland; Folkhälsan Institute of Genetics (M.M., A.-K.A., A.L., A.-E.L.), Helsinki, Finland; Division of Membrane Physiology (Y.F., M.F.), Department of Cell Physiology, National Institute for Physiological Sciences, National Institutes of Natural Sciences, Okazaki, Japan; Department of Physiological Sciences (Y.F., M.F.), School of Life Science, SOKENDAI (The Graduate University for Advanced Studies), Okazaki, Japan; Medical and Clinical Genetics (A.-K.A.), University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Analytic and Translational Genetics Unit (A.P.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston, MA; Program in Medical and Population Genetics (A.P.) and Stanley Center for Psychiatric Research (A.P.), Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, MA; Program in Genetics and Genomics (A.P.), Biological and Biomedical Sciences, Harvard Medical School, Boston, MA; Wellcome Trust Sanger Institute (A.P.), Wellcome Trust Genome Campus, Hinxton, United Kingdom; Psychiatric & Neurodevelopmental Genetics Unit (A.P.), Department of Psychiatry, and Department of Neurology (A.P.), Massachusetts General Hospital, Boston, MA; Department of Pediatric Neurology (H.P., T.L.), Children's Hospital, University of Helsinki and Helsinki University Hospital, Helsinki, Finland; Department of Radiology (L.V.), HUS Medical Imaging Center, Helsinki, Finland; and Family Federation of Finland (M.S.), Helsinki, Finland.
Genetic mutations in ADAM22 cause a severe epilepsy syndrome with rapid brain atrophy. These findings highlight the LGI1-ADAM22 complex
Area of Science:
- Neurogenetics
- Molecular Neuroscience
- Developmental Neuroscience
Background:
- A rare syndrome presents with rapid cerebral atrophy, intractable seizures, and intellectual disability.
- The molecular underpinnings of this severe neurological disorder remain largely unknown.
Purpose of the Study:
- To elucidate the molecular genetic basis of a syndrome characterized by rapidly progressing cerebral atrophy and intractable epilepsy.
- To investigate the functional consequences of identified genetic variants on protein interactions crucial for synaptic function.
Main Methods:
- Exome sequencing and whole-genome SNP genotyping were performed on a patient and their parents.
- Heterologous expression systems were utilized to assess the functional impact of identified mutations in ADAM22.
- Cell surface binding and immunoprecipitation assays were conducted to evaluate LGI1-ADAM22 interactions.
Main Results:
- Compound heterozygous mutations (missense and frameshift) were identified in ADAM22, encoding a postsynaptic receptor for LGI1.
- Both mutant ADAM22 proteins demonstrated impaired binding to LGI1.
- The frameshift mutant ADAM22 also exhibited reduced binding to PSD-95, a postsynaptic scaffolding protein.
Conclusions:
- Mutations in ADAM22 disrupt the LGI1-ADAM22 ligand-receptor complex, likely causing the observed epilepsy syndrome and rapid cortical atrophy.
- These findings underscore the critical role of the LGI1-ADAM22 complex in postnatal synaptic maturation and nervous system development.
- The identified mutations likely result in a hypomorphic rather than a complete loss of function, explaining the patient's survival beyond the early postnatal period.
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