Trisomy of RCAN1 Disrupts Peripheral Nervous System in Down Syndrome

Mouse models of Down syndrome showed up to 3 times the number of RCAN1 compared to normal chromosomes.

Researchers from Johns Hopkins University have linked the gene RCAN1 to impaired peripheral nervous system development in patients with Down syndrome.1

Although most of the research into nervous system abnormalities in Down syndrome has focused on the central nervous system (CNS), those with Down syndrome are known to have dysfunction of the peripheral nervous system (PNS) as well. Diabetes and heart failure are prevalent in this population, and sympathetic nervous system dysfunction has been suspected to be involved, the authors wrote in the paper, which was published in Nature Communications.

“There’s been a whole aspect of the nervous system that has been ignored in Down syndrome, and perhaps in other neurological disorders,” said co-author Rejji Kuruvilla, PhD, in a statement.2

The authors note that animal studies have indicated that nerve growth factor (NGF) is involved in the development of the sympathetic nervous system, with  decreased peripheral nerve innervation demonstrated with ablation of NGF or its receptor, TrkA.

For this study, Ami Patel, a graduate student of the Department of Biology at Johns Hopkins University in Baltimore, MD, and colleagues explored the mechanisms involved in sympathetic innervation loss using human Down syndrome tissue and a mouse model of Down syndrome.

They found that mouse models of Down syndrome demonstrated shorter, less branched sympathetic fibers innervating the target organs. Likewise, splenic and pancreatic tissue from infants with Down syndrome had decreased immunostaining for sympathetic innervation and reduction in tyrosine hydroxylase (TH) immunoreactivity compared to normal tissue (P=0.026 for pancreas; P=0.01 for spleen; t-test n=3). The investigators also found reduced endocytosis of TrK receptors in the mouse model.

The researchers found that RCAN1, which regulates calcineurin 1, occurs at 3 times the number found in normal chromosomes. Excess copies of RCAN1 appear to inhibit calcineurin-mediated dynamin1 dephosphorylation and thus interfere with endocytosis of TrkA receptors. To further understand the role of RCAN1,  the reserachers genetically corrected the level of RCAN1 and found that receptor trafficking as well as innervation and neuron survival improved.

 “Down syndrome is a complex genetic disorder believed to arise from the trisomy of many genes. Here, we define that increased dosage of a single gene, RCAN1, exerts pronounced effects on the development of sympathetic neurons,” the authors wrote.1

“When you think about therapeutic interventions that could affect life quality, it’s important to not ignore this important aspect of the nervous system,” Dr Kuruvilla said.2


  1. Patel A, Yamashita N, Ascaño M, et al. RCAN1 links impaired neurotrophin trafficking to aberrant development of the sympathetic nervous system in Down syndrome. Nat Commun. 2015;6:10119.
  2. Research Traces Cause of Organ Dysfunction in Down Syndrome. Johns Hopkins Office of Communications; December 14, 2015. Available at: Accessed December 22, 2015.