Mental Retardation, X-Linked, Syndromic 32

A number sign (#) is used with this entry because of evidence that syndromic X-linked mental retardation-32 (MRXS32) is caused by mutation in the CLIC2 gene (300138) on chromosome Xq28. One such family has been reported.

Clinical Features

Takano et al. (2012) reported a family (K8015) in which 2 brothers had profound mental retardation. Both had delayed psychomotor development beginning in infancy and had little or no speech development. Both also had seizures, large joint contractures, and abnormal positioning of the thumbs. One patient had hydrocephalus and 1 had spastic quadriplegia as an adult. Both patients were confined to a residential institution in childhood. Cardiac problems became apparent in their forties. Both had an enlarged heart resulting in congestive heart failure and valvular insufficiency, and 1 patient had atrial fibrillation. The patients did not have apparent abnormalities of skeletal muscles.

Inheritance

The transmission pattern of MRX32 in family K8015 reported by Takano et al. (2012) was consistent with X-linked recessive inheritance.

Molecular Genetics

Using exome capture and deep sequencing of genes on the X chromosome in a family with X-linked syndromic mental retardation, Takano et al. (2012) identified a missense mutation in the CLIC2 gene (H101Q; 300138.0001). The mother, who carried the mutation in heterozygous state, was considered by family members to have a learning disability. In vitro functional expression studies showed that the mutant protein had increased thermal stability compared to wildtype and caused an increase in both the skeletal RYR1 (180901) and cardiac RYR2 (180902) channels being in the open probability states, which was a reversal of the effect of wildtype CLIC2. Three-dimensional predictions indicated that the H101Q mutation affected the binding affinity to RYR channels, resulting in stronger and more stable binding compared to wildtype. Overall, the data suggested that mutant CLIC2 would stimulate the release of calcium by keeping the RYR channels in the open state, resulting in overly active RYR2 in heart muscle with excess potential firing in those cells.