Whole Exon Deletion in the GFAP Gene Is a Novel Molecular Mechanism Causing Alexander Disease

Author:

Green Lydia1,Berry Ian2,Childs Anne-Marie1,McCullagh Helen1,Jose Sandhya3,Warren Dan4,Craven Ian4,Camm Nick2,Prescott Katrina5,van der Knaap Marjo6,Sheridan Eamonn7,Livingston John1

Affiliation:

1. Department of Paediatric Neurology, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

2. Leeds Genetics Laboratory, St. James's University Hospital, Leeds, United Kingdom

3. Hull Royal Infirmary, Hull, United Kingdom

4. Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom

5. Department of Clinical Genetics, Leeds, United Kingdom

6. Department of Child Neurology, VU University Medical Center, Amsterdam, The Netherlands

7. School of Medicine, University of Leeds, St. James's University Hospital, Leeds, United Kingdom

Abstract

AbstractAlexander disease (AD) is a leukodystrophy caused by heterozygous mutations in the gene encoding the glial fibrillary acidic protein (GFAP). Currently, de novo heterozygous missense mutations in the GFAP gene are identified in over 95% of patients with AD. However, patients with biopsy-proven AD have been reported in whom no GFAP mutation has been identified. We report identical twin boys presenting in infancy with seizures and developmental delay in whom MR appearances were suggestive of AD with the exception of an unusual, bilateral, arc of calcification at the frontal white–gray junction. Initial mutation screening of the GFAP gene did not identify a mutation. Whole exome sequencing in both brothers revealed a de novo heterozygous in-frame deletion of the whole of exon 5 of the GFAP gene. Mutations in the GFAP gene are thought to result in a toxic effect of mutant GFAP disrupting the formation of the normal intermediate filament network and resulting in Rosenthal fiber formation, which has hitherto not been linked to exonic scale copy number variants in GFAP. Further studies on mutation negative AD patients are warranted to determine whether a similar mechanism underlies their disease.

Publisher

Georg Thieme Verlag KG

Subject

Clinical Neurology,General Medicine,Pediatrics, Perinatology, and Child Health

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