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
✍ Scribed by Céline Bonnet; Alice Masurel-Paulet; Asma Ali Khan; Mylène Béri-Dexheimer; Patrick Callier; Francine Mugneret; Christophe Philippe; Christel Thauvin-Robinet; Laurence Faivre; Philippe Jonveaux
- Publisher
- John Wiley and Sons
- Year
- 2011
- Tongue
- English
- Weight
- 245 KB
- Volume
- 33
- Category
- Article
- ISSN
- 1059-7794
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✦ Synopsis
GRIA3 encodes glutamate receptor ionotropic AMPA (alpha-amino-3-hydroxy-5-methyl-4isoxazolepropionic 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.