Mental Retardation, X-Linked, Syndromic, Wu Type

A number sign (#) is used with this entry because this form of X-linked mental retardation (MRXSW) is caused by mutation in the GRIA3 gene (305915).

Clinical Features

Wu et al. (2007) identified 3 families in which X-linked mental retardation clearly segregated with mutations in the GRIA3 gene. The probands were identified from a group of 400 unrelated males with MRX who were specifically screened for GRIA3 mutations. In 1 family, 2 affected individuals had moderate MR, macrocephaly, seizures, myoclonic jerks, and autistic behavior (G833R; 305915.0001). Four patients from a second family with had moderate MR and asthenic body habitus (R631S; 305915.0002). Two patients from a third family had mild to moderate MR, asthenic body habitus, poor muscle bulk, distal muscle weakness, and hyporeflexia (M706T; 305915.0003). Three additional unrelated patients with a 0.4-Mb deletion (305915.0004) had moderate MR, reduced muscle bulk, and hyporeflexia.

Bonnet et al. (2009) reported a family with X-linked mental retardation associated with a partial duplication of the GRIA3 gene. There were 2 affected brothers, last examined at age 20 years. Both had delayed psychomotor development since infancy with severely delayed and poor language acquisition. Brain MRI was normal in 1 and showed a retrocerebellar cyst in the other. The patient with the cyst also had some dysmorphic features, including narrow palate, prominent incisors, short philtrum, and uplift of ear lobules. He also had behavioral problems with fits of anger. The mother, who also carried the partial duplication, was considered affected, with language and learning disabilities, facial hypotonia, and a moderately short upper lip.

Philips et al. (2014) reported 3 affected males from a Finnish family (D174) with MRX94. They had severe mental retardation with autistic features, epilepsy, short stature, and behavioral problems, including self-injury and aggressive outbursts. Dysmorphic features included brachycephaly, deep-set eyes, and prominent supraorbital ridges.

Cytogenetics

Gecz et al. (1999) reported a 20-year-old Iranian woman with mental retardation and features of bipolar disorder associated with an apparently balanced translocation t(X;12)(q24;q15). She had delayed development in infancy with 2 seizures, and developed a bipolar affective disorder with cyclic vomiting as a presenting symptom at age 12. By FISH, Gecz et al. (1999) found that the X-chromosome breakpoint mapped within the Xq24 region and disrupted the GRIA3 gene. A large set of 373 individuals from 40 pedigrees segregating bipolar disorder were genotyped using closely linked and intragenic GRIA3 STR markers, but there was no evidence of linkage.

Chiyonobu et al. (2007) reported a 4-year-old Japanese boy with nonsyndromic mental retardation who had a submicroscopic chromosome Xq25 copy number gain detected by array CGH analysis. Molecular characterization revealed a partial tandem duplication of the GRIA3 gene affecting exons 1 to 6. His unaffected mother was a carrier of the duplication and showed completely skewed X inactivation in peripheral lymphocytes. RT-PCR analysis showed decreased GRIA3 mRNA transcripts in lymphoblastoid cells derived from both the son and mother.

In affected members of the family reported by Bonnet et al. (2009), array comparative genomic hybridization detected 2 duplications at chromosome Xq25. One was 270.5 kb and involved the GRIA3 gene, starting about 3 kb before exon 1 and ending in intron 12, about 6 kb before exon 13. The second duplication was 269.97 kb in length, was found to be 400 kb distal to the first duplication, and included the entire BIRC4 gene (XIAP; 300079) and the first 4 exons of the STAG2 gene (300826). RT-PCR studies of the first duplication identified 3 different transcripts, with duplication of exons 1 to 12, exons 2 to 12, and exons 3 to 12, all of which resulted in a frameshift and premature termination after exon 12, with lack of synthesis of a functional AMPA receptor. The hypothetical truncated protein would lack the S2 segment and TM4 domain. X-inactivation studies showed that the affected mother had a random pattern (23 to 77%), but her unaffected daughter, who also carried the mutation, had a skewed pattern (3 to 97%). Bonnet et al. (2009) could not exclude a role for the second distal duplication, but concluded that the phenotype was mainly due to disruption of the GRIA3 gene.

Bonnet et al. (2012) reported a boy with severe mental retardation, axial hypotonia, spasticity, and seizures associated with a hemizygous 970-kb duplication at Xq24-q25 located in a gene desert 874 kb upstream of the GRIA3 gene. The duplication was inherited from his unaffected mother, who showed skewed X inactivation (10-90%). RT-PCR analysis of the patient's cells showed complete loss of GRIA3 expression, but no mutations were found within the gene. Comparative genomic analysis showed a 2,268-bp evolutionarily conserved region centromeric to the duplicated region that could be a critical transcription factor binding site for GRIA3 expression. Bonnet et al. (2012) suggested that the duplication repositioned a potential distant regulator of the GRIA3 gene, resulting in GRIA3-linked mental retardation.

Molecular Genetics

Wu et al. (2007) identified 3 families in which X-linked mental retardation clearly segregated with mutations in the GRIA3 gene (305915.0001-305915.0003). In vitro functional expression studies showed that the mutant proteins interfered with proper kinetics of the glutamate AMPA3 receptor.

In 3 affected males from a large Finnish family (D174) with MRX94, Philips et al. (2014) identified a missense mutation in the GRIA3 gene (G630R; 305915.0005). The mutation was found by X-chromosome exome sequencing in 14 Finnish families with X-linked mental retardation.