Contribution of CYLN2 and GTF2IRD1 to neurological and cognitive symptoms in Williams Syndrome

Abstract Williams Syndrome (WS, [MIM 194050]) is a disorder caused by a hemizygous deletion of 25–30 genes on chromosome 7q11.23. Several of these genes including those encoding cytoplasmic linker protein-115 ( CYLN2 ) and general transcription factors ( GTF2I and GTF2IRD1 ) are expressed in the brain and may contribute to the distinct neurological and cognitive deficits in WS patients. Recent studies of patients with partial deletions indicate that hemizygosity of GTF2I probably contributes to mental retardation in WS. Here we investigate whether CYLN2 and GTF2IRD1 contribute to the motoric and cognitive deficits in WS. Behavioral assessment of a new patient in which STX1A and LIMK1 , but not CYLN2 and GTF2IRD1 , are deleted showed that his cognitive and motor coordination functions were significantly better than in typical WS patients. Comparative analyses of gene specific CYLN2 and GTF2IRD1 knockout mice showed that a reduced size of the corpus callosum as well as deficits in motor coordination and hippocampal memory formation may be attributed to a deletion of CYLN2 , while increased ventricle volume can be attributed to both CYLN2 and GTF2IRD1 . We conclude that the motor and cognitive deficits in Williams Syndrome are caused by a variety of genes and that heterozygous deletion of CYLN2 is one of the major causes responsible for such dysfunctions.