Haploinsufficiency of DNA Damage Response Genes and their Potential Influence in Human Genomic Disorders

Abstract

Genomic disorders are a clinically diverse group of conditions caused by gain, loss or re-orientation of a genomic region containing dosage-sensitive genes. One class of genomic disorder is caused by hemizygous deletions resulting in haploinsufficiency of a single or, more usually, several genes. For example, the heterozygous contiguous gene deletion on chromosome 22q11.2 causing DiGeorge syndrome involves at least 20-30 genes. Determining how the copy number variation (CNV) affects human variation and contributes to the aetiology and progression of various genomic disorders represents important questions for the future. Here, I will discuss the functional significance of one form of CNV, haploinsufficiency (i.e. loss of a gene copy), of DNA damage response components and its association with certain genomic disorders. There is increasing evidence that haploinsufficiency for certain genes encoding key players in the cells response to DNA damage, particularly those of the Ataxia Telangiectasia and Rad3-related (ATR)-pathway, has a functional impact. I will review this evidence and present examples of some well known clinically similar genomic disorders that have recently been shown to be defective in the ATR-dependent DNA damage response. Finally, I will discuss the potential implications of a haploinsufficiency-induced defective DNA damage response for the clinical management of certain human genomic disorders.

Keywords: ATR; DNA damage response; genomic disorders.; haploinsufficiency.

Fig. (1)

A). Chromosome 17 karyotype from a normal and MDLS individual. B). A view of a single chromatid of chromosome 17p13.3 showing the order of the genes in this region from the centromere (Cen) to the telomere (Tel). The dotted lines denote the deletions (hemizygous) of various sizes associated with respective patients listed on the left hand side. Con-MR is a patient with a telomeric deletion. This patient exhibits mental retardation but normal stature and head circumference. ILS represents an Isolated Lissencephaly Sequence patient deleted for PAFAH1B1/Lis1 alone. ILS+ denotes Isolated Lissencephaly Sequence patients with increasing deletions telomeric from PAFAH1B1/Lis1. MDLS represents Miller-Dieker Lissencephaly.