Neighboring mutations in gene may spawn separate conditions


Spectrum | Oksana Grivina

[Source: Spectrum | Jessica Wright, January 25, 2016]


Two seemingly similar mutations in the SHANK3 gene have divergent effects on the brain and behavior, according to a mouse study published 6 January inNeuron1. The findings may help explain why one mutation is associated with autism, whereas the other has ties to schizophrenia.

SHANK3 is on a growing list of genes linked to autism, many of which also have ties to other neuropsychiatric disorders. The new study serves as a reminder that compiling lists of risk genes is just the first step toward understanding these complex conditions.

“If we really want to model human disease — to study molecular, cellular and behavioral defects — we have to consider what kinds of mutations they are,” says lead researcher Guoping Feng, professor of brain and cognitive sciences at the Massachusetts Institute of Technology. “We have to painstakingly look at them individually.”

Roughly 1 percent of people with autism and 2 percent of people with both autism and intellectual disability have mutations in SHANK3. Studies in mice suggest these mutations have a wide range of effects, depending on where they land in the gene.

In the new study, Feng and his team engineered mice that carry one of two SHANK3 mutations. One replicates a mutation that scientists previously identified in two brothers who have both autism and severe intellectual disability. The other mimics a variant found in three brothers diagnosed with schizophrenia between the ages of 16 and 21.

The mutations are just 325 nucleotides apart — close neighbors in genetic terms. And both change the genetic code by a single letter in a way that effectively cuts short the SHANK3 protein. The protein ordinarily serves as a molecular bridge that links key parts of the signal-receiving ends of neurons.

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