title: A neurodevelopmental disorder with a nonsense mutation in the Ox-2 antigen domain of the amyloid precursor protein (APP) gene.
abstract: We report a patient, an infant with a neurodevelopmental disorder manifesting intractable complex partial epilepsy, bull's eye maculopathy, microcephaly, bilateral cataracts, truncal hypotonia, and spasticity of all four extremities. Sequencing of genomic DNA revealed mutations in (a) exon 8 (Ox-2 antigen domain) of the amyloid precursor protein (APP) gene: c.1075C>T, p.Arg359*(b) exon 8 of the senataxin (SETX) gene: c.4738C>T, p.Arg1580Cys, and (c) exon 2 of the ceroid-lipofuscinosis, neuronal 8 (CLN8) gene: c.685C>G, p.Pro229Ala. Using a quantitative method for measurement of various APP-mRNA isoforms, we found that the APP-mRNA isoform of 624 bp with a deletion starting after 49 bp of the 5' end of exon 3 followed by a complete deletion of exons 4-15, mutations in exon 1: c.22C>T, p.L18F, and exon 3: c.269A>G, p.Q90R encoding APP207isoform was the most abundant one, and would appear to be responsible for the clinical manifestations. This is the first example that may underline the role of the epigenetic regulation in the expression of APP gene leading to a neurodevelopmental disorder resulting from a nonsense mutation in the Ox-2 antigen domain.
authors.affiliation: a Department of Medicine, Biochemical Genetics and Metabolism , The Mitochondrial and Metabolic Disease Center, School of Medicine, University of California , San Diego, San Diego , CA , USA.|b Department of Pediatrics , University of California, San Diego, School of Medicine , San Diego, La Jolla , CA , USA.
authors.forename: Khue Vu
authors.initials: KV
authors.lastname: Nguyen
authors.affiliation: c Division of Metabolic Disorders , Children's Hospital of Orange County , Orange , CA , USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Leydiker
authors.affiliation: c Division of Metabolic Disorders , Children's Hospital of Orange County , Orange , CA , USA.
authors.forename: Raymond
authors.initials: R
authors.lastname: Wang
authors.affiliation: c Division of Metabolic Disorders , Children's Hospital of Orange County , Orange , CA , USA.
authors.forename: Jose
authors.initials: J
authors.lastname: Abdenur
authors.affiliation: b Department of Pediatrics , University of California, San Diego, School of Medicine , San Diego, La Jolla , CA , USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Nyhan
mesh_terms: D016564:Amyloid beta-Protein Precursor / Q000737:chemistry / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D018389:Codon, Nonsense; D003241:Consanguinity; D044127:Epigenesis, Genetic; D005091:Exons; D005260:Female; D017353:Gene Deletion; D006801:Humans; D008297:Male; D009154:Mutation; D065886:Neurodevelopmental Disorders / Q000235:genetics*; D010375:Pedigree; D012333:RNA, Messenger / Q000235:genetics
chemical_list: D016564:Amyloid beta-Protein Precursor; D018389:Codon, Nonsense; D012333:RNA, Messenger
keywords: Kinetic method; RT-PCR technique; amyloid precursor protein; epigenetics; neurodevelopmental disorder; nonsense mutation in the Ox-2 antigen domain; sequencing