The de novo chromosome 16 translocations of two patients with abnormal phenotypes (mental retardation and epilepsy) disrupt the A2BP1 gene

Abstract

The 16p13.3 breakpoints of two de novo translocations of chromosome 16, t(1;16) and t(14;16), were shown by initial mapping studies to have physically adjacent breakpoints. The translocations were ascertained in patients with abnormal phenotypes characterized by predominant epilepsy in one patient and mental retardation in the other. Distamycin/DAPI banding showed that the chromosome 1 breakpoint of the t(1;16) was in the pericentric heterochromatin therefore restricting potential gene disruption to the 16p13.3 breakpoint. The breakpoints of the two translocations were localized to a region of 3.5 and 115 kb respectively and were approximately 900 kb apart. The mapping was confirmed by fluorescence in situ hybridization (FISH) of clones that spanned the breakpoints to metaphase spreads derived from the patients. The mapping data showed both translocations disrupted the ataxin-2-binding protein 1 (A2BP1) gene that encompasses a large genomic region of 1.7 Mb. A2BP1 encodes a protein that is known to interact with the spinocerebellar ataxia type 2 (SCA2) protein. It is proposed that disruption of the A2BP1 gene is a cause of the abnormal phenotype of the two patients. Ninety-six patients with sporadic epilepsy and 96 female patients with mental retardation were screened by SSCP for potential mutations of A2BP1. No mutations were found, suggesting that disruption of the A2BP1 gene is not a common cause of sporadic epilepsy or mental retardation.Keywords A2BP1 AE Chromosome 16 AE Spinocerebellar ataxia binding protein AE De novo translocation De novo chromosome rearrangements are associated with an increased risk of congenital malformations (Warburton 1991). Disruption of a critical gene at the translocation breakpoint is thought to be the basis for this increased risk. We report the finding of two patients with de novo translocations that involve a breakpoint at 16p13.3, show that there is disruption of the ataxin-2-binding protein 1 (A2BP1) gene by these 16p13.3 breakpoints, and propose that the disruption of A2BP1 is the basis for the patients' clinical phenotypes.The first of the de novo translocations was ascertained in a boy with severe intellectual and developmental retardation (developmental skills at 2-2.5 years when examined at 4 years 11 months) but with no dysmorphic features other than strabismus and down-turned angles of the mouth. There was a single recorded episode of fitting at 5 days old. Chromosome analysis showed at(1;16)(q12;p13.3). Parental karyotypes were normal. Both parents were considered to have mild intellectual disability. Distamycin A/DAPI, which stains the pericentromeric heterochromatin of chromosomes 1 and 16, was used to stain the chromosomes (Fig. 1a). The der(1)t(1;16) showed a single band; the der(16) had two bands, one representing the 16 heterochromatin and the other at the 16p13.3 breakpoint derived from chromosome 1 heterochromatin (Fig. 1a). This observation is consistent with the location of the chromosome 1 breakpoint within the 1q12 heterochromatin. If the boy'...

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