Down Syndrome and Vascular Disease: DSCR1 and NFAT Signaling

Abstract

Down Syndrome (DS) is one of the most common genetic disorders to date, occurring in 1 out of every 800-1000 live births (Egan et al. 2004; Roizen & Patterson, 2003; Stoll et al. 1990). DS patients often display several developmental and cognitive deficiencies. Common phenotypes of DS patients include congenital heart disease, dysmorphic physical features, and early-onset Alzheimer’s disease (AD). Since the discovery in 1959 that DS occurs from an extra copy of human chromosome 21 (hChr21) (Lejeune J, Gautier & Turpin, 1959), questions arose whether a 1.5-fold increase in a gene or set of genes were responsible for the phenotypes associated with DS. Sequence analysis of hChr21 indentified over 225 genes and/or predicted genes (Hattori et al. 2000). With the recent advances in sequencing, the gene content of hChr21 is now estimated to exceed 300 genes (Roizen & Patterson, 2003). While typically characterized by complete trisomy of hChr21, several DS cases, however, demonstrate that partial trisomy of hChr21 is enough to elicit the phenotypes associated with DS (Stoll et al. 1990), hence arising the concept of a Down Syndrome Critical Region (DSCR). The DSCR theory suggests that enhanced expression of a few genes located in this critical chromosomal region (between markers D21S17 and D21S55 (Delabar et al. 1993; Korenberg et al. 1994)) are responsible for some, if not all, of the features of DS. Olson LE et al show, however, that triplication of this region alone is not enough to fully manifest the phenotypes associated with DS (Olson et al. 2004; Olson et al. 2007). These findings contradict the longstanding DSCR theory, indicating that the genetic instability seen with hChr21 triplication is not merely from excess gene expression. Rather, the functional interactions occurring within a set of overexpressed genes may explain the various phenotypes observed in DS. Many of the triplicate genes on hChr21 are implicated in several diseases. Cohorts of genes, interestingly, have been associated with pathologies that appear to be more common for DS individuals. A group of at least 16 genes on hChr21 have been correlated with a role in energy and reactive oxygen species (ROS) metabolism (Roizen & Patterson, 2003). Several studies have linked mitochondrial dysfunction and metabolic disorders with DS (Arbuzova, Hutchin & Cuckle, 2002). In vitro, DS neurons were observed to have 3to 4-fold increases in reactive oxygen species compared to control cells, with elevated rates of consequent cell apoptosis (Busciglio & Yankner, 1995). Degeneration of DS neurons was rescued by administration of free-radical scavengers, suggesting DS neurons are unable to efficiently metabolize ROS. DS patients are also evidenced to have increased mitochondrial superoxide