Genes speak to each other in their own molecular dialect. By tracking one such conversation, scientists have identified a genetic relationship that may contribute to the common childhood language disorder known as specific language impairment, or SLI.
A gene called FOXP2 communicates with another gene, contactin-associated protein-like 2, or CNTNAP2. That process hampers the CNTNAP2 ability to make a protein that helps to direct prenatal and later brain growth, say geneticist Simon Fisher of the University of Oxford, England, and his colleagues.
What’s more, children with specific language impairment frequently inherit certain versions of the CNTNAP2 gene, Fisher’s team reports online November 5 in The New England Journal of Medicine. The team suspects that these CNTNAP2 variations are particularly susceptible to FOXP2 regulation.
Analyses of the neural consequences of CNTNAP2’stweaking by FOXP2 should begin to illuminate the roots of language problems that characterize not only SLI but also other childhood disorders, such as autism, the researchers assert.
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Language problems characteristic of autism closely resemble SLI. “The same genetic effects on language impairments can operate across distinct developmental disorders,” Fisher says.
Fisher’s new study “shifts the focus from a ‘language gene’ to ‘networks of language-related genes,’ ” comments developmental psycholinguist Mabel Rice of the University of Kansas in Lawrence. Rice agrees with Fisher that common genetic pathways may underlie language impairments observed in different developmental disorders.
In defense of that possibility, Fisher notes that studies published earlier this year by two separate teams found an association between CNTNAP2 variants and autism. Those researchers also noted that high levels of CNTNAP2’s brain protein accumulate in language-related areas, suggesting the protein is related to language development.
Specific language impairment consists of unexplained difficulties in producing and understanding language, often revolving around delayed vocabulary and grammar skills in healthy, intelligent children. An estimated 7 percent of 5- to 6-year-olds exhibit SLI.
Since 2001, researchers have tried and failed to link FOXP2 variants directly to specific language impairment, without considering how FOXP2 regulates other genes. That quest was inspired by a report that members of an extended family diagnosed with symptoms of SLI and with speech and intellectual impairments had inherited a specific FOXP2 mutation. It turned out that this genetic alteration, which deactivates the gene, occurs extremely rarely and is not a cause of SLI.
Psycholinguist Karin Stromswold of Rutgers University in New Brunswick, N.J., calls the new findings “a bold step in the elucidation of the genetic underpinnings of language impairment.” She emphasizes that the new study is also a first step toward examining the roles of numerous FOXP2-regulated genes in language disorders.
Versions of FOXP2 appear in many animals, including primates, birds, bats and mice. This gene has been linked to song production by birds, learning of movement sequences by mice and use of echolocation by bats.
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In earlier studies of human neurons grown in the laboratory, Fisher’s group identified more than four dozen brain-related genes potentially regulated by FOXP2.
In their new study of genetic material isolated from laboratory-grown brain cells, the researchers found spots on the CNTNAP2 gene that received FOXP2’s protein. CNTNAP2’sability to generate its own protein in these human neurons dropped sharply when the regulatory gene’s protein was present.
A second phase of the investigation examined CNTNAP2 mutations in the members of 184 nuclear families. Each family consisted of two parents and as many as four children, at least one of whom had been diagnosed with specific language impairment before entering the study. Family members who performed especially poorly on a test of ability to repeat spoken nonsense words received an SLI diagnosis from Fisher’s group. Difficulty with this task is a strong marker of SLI, Fisher says.
Participants who carried either one or two copies of certain CNTNAP2 variants displayed specific language impairment more frequently than did those who lacked the same variants. One key set of CNTNAP2 mutations occurred in 40 percent of those who scored extremely poorly on the nonsense-word task, versus 29 percent of those who scored extremely well on the same task.
It will be important to determine whether brain effects of the FOXP2– CNTNAP2 pathway promote all or only some components of SLI, Rice notes. Other evidence suggests that different genetic roots influence difficulties in repeating nonsense words versus struggling with vocabulary and grammar.
“The genetics approach used in Fisher’s study is like opening a new bag of tools to sort out the ways different genes can interact to influence language acquisition and impairment,” Rice says.