title: Exploring the potential role of disease-causing mutation in a gene desert: duplication of noncoding elements 5' of GRIA3 is associated with GRIA3 silencing and X-linked intellectual disability.
abstract: GRIA3 encodes glutamate receptor ionotropic AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) subunit 3 and has been previously involved in X-linked intellectual disability (ID). We report on a male proband with ID and epilepsy associated with a duplication mapping within a gene desert, 874-kb upstream of the GRIA3 gene. This 970-kb duplication is maternally inherited. The proband's mother has a skewed X chromosome-inactivation pattern in agreement with her normal cognitive function. Quantitative polymerase chain reaction analysis indicates absence of GRIA3 mRNA in the proband lymphocytes relative to a wild-type control. Centromeric to the duplicated region, comparative genomic analysis showed a 2268-bp evolutionarily conserved region that could be a critical transcription factor binding-site for GRIA3 expression. The repositioning of distant-acting sequences, rather a missense/nonsense mutation, is considered to be causative for GRIA3-linked ID. This study illustrates the importance of high-resolution array-Comparative Genomic Hybridization analysis in exploring the potential role of disease-causing mutation in functional noncoding sequences.
authors: Laboratoire de Génétique, EA 4368, Nancy Université, Centre Hospitalier Universitaire de Nancy, France.
authors: Céline
authors: C
authors: Bonnet
authors: Alice
authors: A
authors: Masurel-Paulet
authors: Asma Ali
authors: AA
authors: Khan
authors: Mylène
authors: M
authors: Béri-Dexheimer
authors: Patrick
authors: P
authors: Callier
authors: Francine
authors: F
authors: Mugneret
authors: Christophe
authors: C
authors: Philippe
authors: Christel
authors: C
authors: Thauvin-Robinet
authors: Laurence
authors: L
authors: Faivre
authors: Philippe
authors: P
authors: Jonveaux
mesh_terms: D020121:5' Untranslated Regions; D002648:Child; D055028:Comparative Genomic Hybridization; D005091:Exons; D020440:Gene Duplication; D020868:Gene Silencing; D040181:Genetic Diseases, X-Linked / Q000235:genetics*; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics*; D008297:Male; D009154:Mutation; D018091:Receptors, AMPA / Q000235:genetics*; D049951:X Chromosome Inactivation
chemical_list: D020121:5' Untranslated Regions; D018091:Receptors, AMPA; C104723:glutamate receptor ionotropic, AMPA 3