CNTNAP2 (Nov. 5, 2008) (Contactin associated protein-like 2)
Domain-Specificity of Language Gene?
Lenneberg (1967) pp. 248-254
The FOXP2 Story 1996-2001
A single family with speech abnormalities may hold one of the keys to the origin of human culture
The trail to the new gene, known as FOXP2, began in 1996 when Professor Monaco was approached by clinicians working at the
About half the family, which spans three generations, suffer from the disorder. "They have trouble controlling fine movements in the lower half of their face, and this gives them problems when making the complicated sounds necessary for speech," explains Dr Fisher. In addition to this problem, they have a variety of problems in both spoken and written language and grammar. "For example," says Dr Fisher, "if you ask them to write down as many words as they can think of beginning with a particular letter, they don't do very well - and that defect is clearly not related to articulation."
Dr Fisher and Cecilia Lai, a colleague in Professor Monaco's laboratory, embarked on the hunt for the defective gene in the KE family and successfully tracked it down with the help of molecular signposts or 'markers' to a region on chromosome 7 containing between 50 and 100 genes. "We went through every candidate gene in the region relating to brain function," says Dr Fisher, "looking through 20 and keeping another 50 or so on the backburner." Then the trawl was cut short by a stroke of luck.
"We were on the look-out for individuals with a speech disorder who had a chromosomal abnormality," explains Dr Fisher, "because there is a history of these being involved in the mapping of single gene disorders such as Duchenne muscular dystrophy (杜顯氏肌肉萎縮症)." Quite independently, however, a patient was referred to Professor Monaco's group by a local clinician who noted the strong resemblance between her patient's speech problems and those of the unrelated KE family. The problems in the patient, known as 'CS', were associated with a chromosomal abnormality in which large segments from the ends of two different chromosomes had swapped around. One of the chromosomes involved was chromosome 7 and the breakpoint appeared to be close to the region implicated in the KE family.
Perhaps one of the most fascinating lines of research opened up by the discovery of FOXP2 is the evolutionary origins of speech and language. "FOXP2 stands out," says Dr Fisher. "It's very unusual from an evolutionary point of view."
FOXP2, and a speech and language disorder (ScienceNOW, 3 October 2001)
Pedigree diagram showing inheritance of a severe speech and language disorder in the KE family
KE family pedigree: GENETICS OF A SEVERE SPEECH & LANGUAGE DISORDER
Predicted structure of a forkhead box motif, found in the FOX group of transcription factors. The red mark shows the position of a mutation in FOXP2 that is the cause of severe speech and language deficits in a large 3-generation family.
The genes behind learning to speak (Dr Simon Fisher)
FOXP2 is involved in controlling development in different parts of the body, including lung, intestines and cardiovascular tissue, as well as the brain.
FOXP2 belongs to a group of genes that control the developmental programs of cells by switching on or off other genes.
First language gene discovered BBC News, Wednesday, 14 August, 2002
Svante Pääbo (1955-) Watch Svante Pääbo's presentation 1h
Robin Dunbar 1h
With Svante Pääbo's group in Leipzig, he has found that just two amino acids distinguish the FOXP2 protein in humans from the protein in our closest relative, the chimpanzee, and that these amino acids have persisted unchanged in modern humans. FOXP2 appears to have been selected during recent human evolution – sometime within the last 200 000 years.
27th June 2005: That experiment has just been reported. (Shu et al, Altered ultrasonic vocalization in mice with a disruption in the FOXP2 gene (7). They report that: 'Disruption of both copies of the Foxp2 gene caused severe motor impairment, premature death, and an absence of ultrasonic vocalizations that are elicited when pups are removed from their mothers. Disruption of a single copy of the gene led to modest developmental delay but a significant alteration in ultrasonic vocalization in response to such separation. Learning and memory appear normal in the heterozygous animals. Cerebellar abnormalities were observed in mice with disruptions in Foxp2, with Purkinje cells particularly affected. Our findings support a role for Foxp
The eloquent ape: genes, brains and the evolution of language. Fisher SE, Marcus GF. Nat Rev Genet. 2006 Jan;7(1):9-20.
FOXP2 Truncation as a Novel Cause of Developmental Speech and Language Deficits
CNTNAP2 (Nov. 5, 2008) (Contactin associated protein-like 2)
Genetic study provides new insights into molecular basis of language development (Nov. 5, 2008)
Scientists have identified the first gene that is associated with a common childhood language disorder, known as specific language impairment (SLI). The gene – CNTNAP2 (Contactin associated protein-like 2) – has also been recently implicated in autism, and could represent a crucial genetic link between the two disorders.
Although most children acquire proficient spoken language almost automatically and with little conscious effort, a significant number develop unexplained difficulties in producing and understanding language. SLI is the most common such disorder, affecting up to 7% of pre-school children.
In a study published today (Nov.5, 2008) in the New England Journal of Medicine, researchers at the Wellcome Trust Centre for Human Genetics, University of Oxford, discovered that particular variants of the CNTNAP2 gene were significantly associated with language deficits in a large sample of families with SLI.
"It has long been suspected that inherited factors play an important role in childhood language disorders," says Dr Simon E. Fisher, a Royal Society Research Fellow at the Wellcome Trust Centre, who led the research. "But this is the first time that we have been able to implicate variants of a specific gene in common forms of language impairment."
The trail to this new finding began with studies of another language-related gene, called FOXP2, previously found to be mutated in rare cases of a severe speech and language disorder. Versions of FOXP2 are found in many animals, including primates, birds, bats and mice. In birds, for example, it has been linked to song, in mice to learning of sequences of movement, and in bats it may relate to echo-location.
FOXP2 acts to regulate other genes in the brain, switching them on and off. Dr Fisher and colleagues began analysing human neurons grown in the laboratory in order to search for these target genes. They identified CNTNAP2 as a key part of the network.
When the scientists went on to investigate CNTNAP
Recent studies have also implicated CNTNAP
"Our findings suggest that similar changes in the regulation or function of this gene could be involved in language deficits in both SLI and autism," says Dr Fisher. "This supports the emerging view that autism involves the convergence of a number of distinct problems underpinned by different genetic effects."
Professor Dorothy Bishop, a Wellcome Trust Principal Research Fellow at the
"All too often parents of language-impaired children are blamed for their children's difficulties, even though the evidence has been around for a while that genes are implicated. These are important yet neglected disorders that can have long term effects on educational and social outcomes. This landmark study provides an important first step in unravelling the complex biological factors that determine susceptibility to language difficulties."
It is not yet known exactly how changes to CNTNAP2 interfere with language development, but there are some tantalising clues. The gene makes a type of protein called a neurexin ( 1 2 ), which sits in the membranes of neurons, controlling interactions between different cells during the development and wiring up of the nervous system. In early development, the protein appears to be strongly expressed in parts of the human brain which go on to become important for language processing, such as the frontal lobes.
The researchers are now investigating whether variations in CNTNAP2 contribute to natural variation in linguistic abilities in the general population.
"Genes like CNTNAP2 and FOXP2 are giving us an exciting new molecular perspective on speech and language development, one of the most fascinating but mysterious aspects of being human," says Dr. Fisher "There are likely to be more answers buried in our genome. This work promises to shed light on how networks of genes help to build a language-ready brain."
CNTNAP2 & LDB1
“Genome-wide analyses of human perisylvian cerebral cortical patterning” by Abrahams et al., (DOI) who examined human gene expression in frontal vs. superior temporal cortex at a developmental period where neurogenesis and neuronal migration are particularly active. The authors went looking for differential gene expression during a critical developmental time point and in a critical brain region - since the superior temporal cortex is an area that is reliably activated by linguistic tasks as well as social cognition tasks. According to the article, a total of 345 differentially expressed genes were identified, with 61 enriched and 284 down-regulated in superior temporal cortex across two microarray platforms, with 13 genes identified by both microarray array platforms. One of the genes identified is LDB1, a regulator of the asymmetrically expressed LIM domain-only 4 (LMO4) a known mediator of calcium-dependent transcription in cortical neurons and known to regulate thalamocortical connectivity. Another gene, CNTNAP2, a member of the neurexin transmembrane superfamily of proteins that mediate cellular interactions in the nervous system has been previously associated with autism. Both of these genes seem to have important developmental roles and should provide access to the fine-scale wiring that occurs during the development of neural networks involved in language.
Domain-Specificity of Language Gene?
domain-general ancestral inheritance and domain-specific adaptations
The gene genie October 22, 2006 by martinskov
When it was announced in Nature in 2001 that the linguistic disorder displayed by members of an English family known as KE could be traced back to a mutation of a certain gene, FOXP2, Steven Pinker heralded this result as “the dawn of cognitive genetics”. While we are still a long way from being able to link cognitive mechanisms to the function of specific genes, it is certainly true that researchers, these days, are coming increasingly closer to understanding how the genome interfaces with the neural processes underlying cognitive behaviour. Among the many fundamental questions genomic studies are starting weigh in on is how brains have changed in evolutionary lineages, development, and individual differences in cognitive behaviour.
For those interested in this exiting research a number of recent overviews will be of interest. First, the great science journalist Carl Zimmer has a fantastic story in the new (November) issue of National Geographic outlining how evolution forges new complex structures. While Zimmer’s piece doesn’t focus on the evolution of the brain per se, it is a good primer on how evolution in general moves forward by “modifying old genes for new uses and even reusing the same genes in new ways” - i.e., descent with modification, as Darwin called it.
The September 29 issue of Science contained a special section of papers on how genes build the body. It contains, among other fine articles, a very nice story by Elisabeth Pennisi, “Mining the molecules that made our minds”, on current research into the genetics of human brain evolution.
In the October issue of Nature Neuroscience you can find four review papers on the role played by genes in various developmental disorders. Galaburda et al. treats developmental dyslexia, Happé, Ronald & Plomin looks at autism, and Belmonte & Bourgeron deal with Fragile X sydrome. Finally, Gary Marcus and Hugh Rabagliati argues that neither strict modularity, nor a general domain approach, is the right way to understand the relation between genes and behaviour: “On the one hand, descent with modification argues against ’sui generis modularity,’ according to which modules are treated as independent neurocognitive entities that owe nothing to one another; on the other hand, it suggests that exclusive study of overlapping “generalist” contributions is likely to miss some of the most important evolutionary contributions. On this view, language must be understood as the joint product of domain-general ancestral inheritance and domain-specific adaptations.”
Finally, I should mention that the special issue of Cognition on “Genes, brain and cognition” - which I have mentioned earlier - has now been published (October 2006 issue). Its 7 papers will serve anybody from the cognitive sciences well who are interested in knowing more about the relation between genetics and cognition.