ClinGen Dosage Sensitivity Curation Page

GRIA3

  • Curation Status: Complete

Location Information

Select assembly: (NC_000023.10) (NC_000023.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
17568425 Chiyonobu et al. (2007) reported a 498 kb partial tandem duplication involving GRIA3 gene in a male patient with unexplained intellectual disability (ID). The duplication encompassed exons 1-6 with genomic breakpoints chrX:121,756,066-122,254,426 (hg17). The mother was shown to be a carrier. Expression studies of the lymphoblastoid cell revealed remarkably reduced GRIA3 gene transcript in both mother and child. The X chromosome inactivation (XCI) studies in the mother showed a completely skewed XCI (100:0) in lymphocytes, which suggested that the normal X was inactivated. However, given that her cognitive function was reported normal, the GRIA3 expression in the brain was suspected to be at a normal level. The duplication may cause MR due to (1) position-effect resulting in decreased expression of the normal copy of GRIA3 or (2) a dominant-negative effect of the truncated GRIA3 protein resulting in an epigentically modification of the promoter of the entire copy of GRIA3.
19449417 Bonnet et al. (2009) described a 275 kb partial tandem duplication of GRIA3 gene in two brothers (II-1 and II-3) with intellectual disability (ID), developmental delay, behavior troubles and dysmorphic features. The duplication involved the GRIA3 gene with genomic breakpoints chrX:122,143,781-122,419,314 (hg18). The unaffected sister (II-2) also carried the duplication but had completely skewed XCI pattern (3-97%). The duplication was inherited from the mother (I-1) who had language and learning disabilities, facial hypotonia and moderately short upper lip. The clinical features observed in the mother might be due to the random XCI pattern (23-77%) in her lymphocyte. Expression studies showed the presence of three aberrant GRIA3 transcripts with multi-exon duplication (i.e. dup exon 1-12fs, dup exon 2-12fs, and dup exon 3-12fs), which resulted in a frameshift and led to a premature termination codon. As such, the abnormal GRIA3 transcript might produce a non-functional truncated protein (i.e. lacking S2 and TM4 domain) or no protein due to degradation of abnormal protein. Either scenario would lead to a non-functional glutamate receptor ionotropic AMPA subunit 3 (GluR3), which was implicated in learning and memory. There was a second 270 kb duplication in this family that included the BIRC4 and STAG2 genes (chrX:122,812,948-123,082,916 [hg18]), which could not be completely excluded as possible contributing factor to the overall phenotype of the affected members. Because of this, this case will not be scored.
17989220 Wu et al. (2007) reported a 400 kb deletion involving solely the GRIA3 gene (genomic breakpoints 122.00-122.40Mb) detected in a male patient presenting with moderate intellectual disability (ID), poor muscle bulk, muscle weakness, asthetic body habitus and hyporeflexia. The authors also identified four missense mutations involving GRIA3 gene in a study of 400 unrelated probands with X-linked mental retardation. All four missense variants resided to the functional domain of the iGluR3 protein (encoded by the GRIA3 gene). Expression studies in HEK293 cells showed the p.G833R variant (affecting S2 domain) was associated with 78% reduction in receptor protein due to protein misfolding. The p.M706T (affecting M2-M3 link) and p.R631S (affecting S1 - near channel core) variants were associated with minimal or no channel function. In contrast, the p.R450Q (affecting M4) variant was also found in the maternal uncle with apparent normal cognitive function. The functional studies of p.R450Q variant showed a 'distinct kinetic changes in that desensitization was slightly accelerated and recovery from desensitization was drastically slowed.' Hence, it is unclear how the kinetic alterations relate to the ID phenotype in the patient with p.R450Q variant. The author concluded that mutant iGluR3 with altered kinetic properties is associated with moderate cognitive impairment in humans.

Haploinsufficiency phenotype comments:

In addition, Gecz et al. (1999) described a female patient with bipolar affective disorder and intellectual disability. She was a balanced translocation carrier for t(X;12)(q24;q15), where the breakpoint on chromosome X disrupted the GRIA3 gene (at exon 5). Expression studies showed a low level of the normal GRIA3 transcript despite the XCI showed complete inactivation of the normal chromosome X. PMID: 10644433. The authors did not indicate whether or not they mapped the second breakpoint in 12q15, because of this, the evidence is not scored. Philips et al. (2014) (PMID:24721225) studied fourteen Finnish families with two or more affected males presented with intellectual disabilities (ID). One family (D174) had a missense mutation in exon 12 of the GRIA3 gene (c.1888G>C; p.Gly630Arg) involving M2-M3 link domain, which was not found in 135 Finnish controls. The shared phenotype included severe ID with autistic features, epilepsy, short stature and behavioral problems (i.e. self injury and aggressive outbursts). In silico analysis, using the HOPE server, had predicted the mutant residue to be larger than the wild type residue. This might disrupt the contacts with other transmembrane domains or with lipid membrane. Also, it might affect the hydrophobic interactions within the core of the protein or with the membrane lipids. Hamdan et al. (2011) studied ninety five sporadic nonsyndromic intellectual disability (NSID) cases and found one patient with a missense mutation (p.Gly756Cys) involving S2 domain. The mutation was maternally inherited. PMID: 21376300. Hu et al. (2016) studied chromosome X in males with intellectual disability from 405 families using exome sequencing. The study identified a missense mutation in the GRIA3 gene (G>A, p.G721R) in family P176 and a nonsense mutation (G>T, p.E224*) in family N21, which were absent in controls. PMID: 25644381. LaDuca et al. (2017) studied 100 randomly-selected clinical whole exome sequencing (WES) samples and identified one case with a small deletion in the GRIA3 gene (c.2167_2175delGCCCGAGTG, p.A723_V725del) from a patient with intellectual disability. PMID: 28152038.

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity

The loss-of-function and triplosensitivity ratings for genes on the X chromosome are made in the context of a male genome to account for the effects of hemizygous duplications or nullizygous deletions. In contrast, disruption of some genes on the X chromosome causes male lethality and the ratings of dosage sensitivity instead take into account the phenotype in female individuals. Factors that may affect the severity of phenotypes associated with X-linked disorders include the presence of variable copies of the X chromosome (i.e. 47,XXY or 45,X) and skewed X-inactivation in females.