Variation in microdeletions of the cyclic AMP-responsive element-binding protein gene at chromosome band 16p13.3 in the Rubinstein-Taybi syndrome

Abstract

Most reported microdeletions of the CREB-binding protein (CBP) gene in the Rubinstein-Taybi syndrome (RTS) were detected by fluorescence in situ hybridization (FISH) with a single cosmid probe specific to the 3' region of the gene. In order to test the hypothesis that the rate of microdeletion-positive cases would be greater if the entire gene was evaluated, we performed FISH on 66 patients with an established diagnosis of RTS, using a panel of five cosmids that span the CBP gene. Five of 66 patients had deletions by FISH (9%), consistent with those rates reported in various series that ranged between 3-25%. Among our cases, different deletions were observed; one was deleted for the 5' but not the 3' region of the CBP gene (case 055). Other deletions included a total CBP deletion extending from the 5' through the 3' region (case 017), a deletion of all but the 5' region (cases 006 and 060), and an interstitial deletion in the 3' region (case 028). Fine breakpoint mapping with additional cosmid and yeast artificial chromosome (YAC) constructs was performed on these patients. The findings of a partial 5' deletion and of interstitial deletions of the CBP gene add to the known spectrum of mutations of this gene in RTS and demonstrate the need for evaluation of the entire CBP gene region for deletions rather than only the 3' region in RTS patients. These results further suggest that the true rate of microdeletion across the CBP gene detectable by FISH has yet to be established firmly. No phenotypic differences between partial deletion, complete deletion, and nondeletion patients were observed, supporting a haploinsufficiency model for RSTS.

Loss of Heterozygosity and Internal Tandem Duplication Mutations of the CBP Gene Are Frequent Events in Human Esophageal Squamous Cell Carcinoma

“…In humans, germ-line point mutations and microdeletions of the CBP gene have been identified in Rubinstein-Taybi Syndrome patients. This disease is characterized by mental retardation, craniofacial malformations, broad thumbs, broad big toes, and an increased occurrence of malignancy (15,16). CBP has been mapped to human chromosome 16p13.3 (17).…”

Molecular analysis of the CBP gene in 60 patients with Rubinstein-Taybi syndrome

“…BLAST analysis of this sequence allowed us to determine the exact size of intron 2 (39 517 bp), which was not previously known. In addition, we were able to show that the gap remaining in the sequence between cosmids RT203 (LANL cosmid 400H11 or AC004495) and RT166 (LANL cosmid 420F6 or AC005564) 13 was now filled and spanned 11 173 bp. A NIX analysis focused on the unstable region of CBP indicated the presence of a total of 57% interspersed repeats in this region (27.7% of SINEs, 17.8% of LINEs, 0.8% of LTR elements, and 10.7% of MER elements).…”

Epigenetic targets of HDAC inhibition in neurodegenerative and psychiatric disorders

“…Early evidence for a role for epigenetic pathways in brain came from studies showing that the developmental disorders associated with Rubinstein-Taybi Syndrome (RTS) result from heterozygous mutations in the transcriptional coactivator CBP or its homolog p300 [40,41]. RTS is a well-defined inherited, autosomal-dominant disease that occurs once in 125,000 births and accounts for one in 300 patients with mental retardation [42].…”