Excess MicroRNA from Chromosome 21 Causes Down Syndrome Mental Impairment

Some of the neurological impairments typical of Down syndrome (DS) are caused by abnormally high levels of a microRNA (miRNA) that inhibits the manufacture of the protein SNX27 (sorting nexin 27).

DS, also known as trisomy 21, is a chromosomal condition caused by the presence of all or part of a third copy of chromosome 21. It is the most common chromosome abnormality in humans and is typically associated with a delay in cognitive ability and physical growth and a particular set of facial characteristics.

SNX27 is a member of the sorting nexin family, a diverse group of cytoplasmic and membrane-associated proteins involved in endocytosis of plasma membrane receptors and protein trafficking through these compartments. All members of this protein family contain a phosphoinositide binding domain (PX domain). Mice that lack both genes for production of SNX27 have severe neuronal deficits in the hippocampus and cortex while mice with only one SBX27 gene have grossly normal neuroanatomy but have defects in synaptic function, learning, and memory.

Investigators at the Sanford-Burnham Medical Research Institute (La Jolla, CA, USA) analyzed brain tissue from subjects with DS and confirmed that they contained significantly lower levels of SNX27 than was found in normal individuals.

Studies carried out on a DS mouse model revealed that the activity of the SNX27 gene was being regulated by the microRNA miR-155, which is produced on chromosome 21. By having an extra copy of this chromosome an individual with DS generates excess miR-155, which results in abnormally low levels of SNX27 and mental defects.

Additional results published in the March 24, 2013, online edition of the journal Nature Medicine showed that a viral vector containing additional genes for SNX27 production could be inserted into the brains of the DS mice, and that return of SNX27 levels to normal corrected the animals' synaptic and cognitive deficits.

“In the brain, SNX27 keeps certain receptors on the cell surface - receptors that are necessary for neurons to fire properly,” said senior author Dr. Huaxi Xu, professor of neuroscience at the Sanford-Burnham Medical Research Institute. “So, in Down syndrome, we believe lack of SNX27 is at least partly to blame for developmental and cognitive defects.”

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Sanford-Burnham Medical Research