New understanding of genetics behind Noonan Syndrome

Apr 19 2007

Researchers have discovered that the genetic malfunction that causes a form of mental retardation called Noonan Syndrome (NS) produces an imbalance in the genesis of two types of cells in the developing embryonic brain.

This imbalance, they theorize, could explain how the genetic abnormality gives rise to the neural pathology of the disorder. More broadly, they said, the new insight into the mechanism underlying NS could apply to other inherited forms of retardation.

Freda Miller of the Hospital for Sick Children and University of Toronto and colleagues published their findings in the April 19, 2007 issue of the journal Neuron, published by Cell Press.

NS is a relatively common genetic disorder, occurring in one of every 2,500 live births. It is characterized by congenital heart defects, short stature, learning disabilities, and mental retardation. Approximately 50% of NS cases are caused by a genetic mutation in a biochemical switch called SHP-2. SHP-2 is involved in molecular pathways regulating development of brain cells. The NS mutations cause SHP-2 to be constantly activated.

Specifically, SHP-2 plays a role in the pathways governing differentiation of immature precursor cells into neurons and glial cells. Unlike neurons, which conduct nerve impulses, glial cells are supporting cells that surround neurons and insulate them from one another.

In experiments with cultured precursor cells, the researchers found that SHP-2 activates the regulatory pathway that causes genesis of neurons and inhibits the pathway that generates glial cells. And in experiments with both cell cultures and mouse embryos, they found that the same kind of mutation in SHP-2 that can be found in NS patients disrupts the neuron-glial balance by further promoting the formation of neurons and inhibiting glial cell formation.

The researchers also studied the effects of the mutation in mice engineered to mimic the human disorder. Like humans with NS, the mice had only one mutant copy of the SHP-2 gene, while the other was normal. The researchers observed in the animals, brains increases in neuron density and percentage, as well as a large decrease in glial cells called astrocytes.

"Little is known about how genetic perturbations lead to mental retardation," wrote Miller and colleagues. "Here, we have identified a signaling protein, SHP-2, that plays a key role in allowing environmental cues such as growth factors to instruct multipotent precursor cells to generate one cell type versus another. Moreover, we have shown that the same constitutively activated SHP-2 that occurs in a subpopulation of NS patients causes aberrant neural development in mice, providing a potential explanation for the cognitive dysfunction and neuroanatomical perturbations observed in this disorder. Such a mechanism may well generalize to other syndromes where signaling pathways that are important for neural cell genesis are genetically perturbed."

The researchers speculated that ,genetic perturbations such as those seen in NS, or perhaps even in more commonly studied disorders such as Rett Syndrome, might first perturb cell genesis, and then this might in turn alter many later aspects of neural development, ultimately resulting in impaired circuitry and cognitive dysfunction."

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