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Mutations in ROBO3 cause HGPPS
Newsdesk Left temporoparietal junction performs social reasoning The left temporoparietal junction (TPJ) of the brain is vital to our ability to interpret the thoughts, feelings, and mental state of others, according to new research done at the Behavioural Brain Sciences Centre at the University of Birmingham, UK. “Until now, studies with brain-damaged patients have mainly emphasised the role of the frontal lobes in social reasoning”, Dana Samson, one of the investigators of the study, told The Lancet Neurology. Neurologists involved in the diagnosis and rehabilitation of brain-damaged patients should be aware that impaired social reasoning does not only occur following damage to the frontal lobes, she says. Samson’s team compared the false belief reasoning skills of three patients, whose left TPJ had been damaged by a stroke, with three healthy individuals. The participants watched or heard
stories and answered questions about the beliefs of the characters. In one story, the first character puts milk in the fridge and leaves the room, after which another character drinks and disposes of the milk. Participants were asked where the first character thinks the milk is. The stroke patients were unable to correctly infer the characters’ beliefs, whereas the healthy people had no such problem. By use of such tests, Samson and colleagues showed that the left TPJ is needed to understand another person’s belief (Nat Neurosci 2004; published online April 11, DOI: 10.1038/nn1223) . Researchers have used neuroimaging to identify brain areas that are active during social reasoning tasks. However, there has been very little work with patients who have lesions in the main components of this system. “This new finding fits in well with other research which suggests that
such high-level cognitive processes are as basic as seeing the world in colour”, says Uta Frith (Institute of Cognitive Neuroscience, UCL, UK). “Previously these processes had not been considered to depend on their own dedicated brain system, but instead to be some outcome of complex and conscious logical analysis.” Follow-up research to investigate the respective role of the frontal lobes and the TPJ in social reasoning is already underway. Samson’s team also plans to investigate whether the role of the left TPJ in high level reasoning is specific to social ability and whether the left TPJ is responsible for the processing of a person’s own beliefs and mental states. The findings may also have implications for research into the neural basis of disorders, such as autism, that involve difficulties inferring the mental states of others. Gillian Carmichael
Mutations in ROBO3 cause HGPPS 2 years ago, the gene that causes horizontal gaze palsy with progressive scoliosis (HGPPS), a rare autosomal recessive disorder, was linked to a locus on chromosome 11. The same researchers have now identified the gene involved in HGPPS, ROBO3, which encodes an axon-guidance protein that seems to promote midline crossing of neurons in the medulla. Patients with HGPPS have mutations in both alleles of ROBO3 and as a result both the ascending sensory and descending motor pathways fail to decussate in the medulla. Lead investigator Joanna Jen (University of California, Los Angeles, USA) and her colleagues sequenced all 28 exons and flanking introns of ROBO3 in ten HGPPS patients and identified ten different homozygous mutations scattered throughout the gene: one nonsense, one splice site, two frameshift, and six missense mutations. “The requirement that mutations be present on both alleles of ROBO3 for the manifestations of HGPPS to occur
328
suggests that the mutations cause loss of gene function”, say the authors. The researchers also did high resolution MRI studies in eight patients to characterise the neuroanatomical deficits. They found that the medulla was abnormally butterfly-shaped, with anterior flattening and an unusual midline cleft; abnormal flattening in the basis pontis was also seen, as was hypoplasia in the pontine tegmentum. Somatosensory and motor evoked potential studies in four patients showed abnormally reversed lateralisation of responses, indicating uncrossed ascending dorsal column medial-leminiscal sensory pathways and descending corticospinal pathways (Science; published online April 22, DOI: 10.1126/science.1096437). “It is simply amazing that the sensorimotor projections are uncrossed in HGPPS patients, who, remarkably, demonstrate no motor or sensory deficits”, says Jen, whose international network of clinicians have now identified ten con-
sanguineous families with HGPPS. “Furthermore, the brainstem appears malformed in HGPPS patients, indicating that aberrant crossing affects normal brainstem morphogenesis. ROBO3 is a member of the roundabout family of transmembrane receptors. Intriguingly, most robo proteins in mice and drosophila mediate midline repulsion of axons, rather than promoting midline crossing like ROBO3. However, the murine homologue to ROBO3 (Robo3) has recently been shown to promote midline crossing in mouse hindbrain and spinal cord (Cell 2004; 117: 157–69). Robo3 does this by acting upstream of Robo1 to prevent sensitivity of Robo1 to slits, which are midline repellents. “The most immediately apparent phenotype of the mutant embryos was the inability of their spinal cords to stay attached at the ventral midline when dissected , indicating a thinned or fragile floor plate”, say the authors of the Cell paper. James Butcher
THE LANCET Neurology Vol 3 June 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.
stories and answered questions about the beliefs of the characters. In one story, the first character puts milk in the fridge and leaves the room, after which another character drinks and disposes of the milk. Participants were asked where the first character thinks the milk is. The stroke patients were unable to correctly infer the characters’ beliefs, whereas the healthy people had no such problem. By use of such tests, Samson and colleagues showed that the left TPJ is needed to understand another person’s belief (Nat Neurosci 2004; published online April 11, DOI: 10.1038/nn1223) . Researchers have used neuroimaging to identify brain areas that are active during social reasoning tasks. However, there has been very little work with patients who have lesions in the main components of this system. “This new finding fits in well with other research which suggests that
such high-level cognitive processes are as basic as seeing the world in colour”, says Uta Frith (Institute of Cognitive Neuroscience, UCL, UK). “Previously these processes had not been considered to depend on their own dedicated brain system, but instead to be some outcome of complex and conscious logical analysis.” Follow-up research to investigate the respective role of the frontal lobes and the TPJ in social reasoning is already underway. Samson’s team also plans to investigate whether the role of the left TPJ in high level reasoning is specific to social ability and whether the left TPJ is responsible for the processing of a person’s own beliefs and mental states. The findings may also have implications for research into the neural basis of disorders, such as autism, that involve difficulties inferring the mental states of others. Gillian Carmichael
Mutations in ROBO3 cause HGPPS 2 years ago, the gene that causes horizontal gaze palsy with progressive scoliosis (HGPPS), a rare autosomal recessive disorder, was linked to a locus on chromosome 11. The same researchers have now identified the gene involved in HGPPS, ROBO3, which encodes an axon-guidance protein that seems to promote midline crossing of neurons in the medulla. Patients with HGPPS have mutations in both alleles of ROBO3 and as a result both the ascending sensory and descending motor pathways fail to decussate in the medulla. Lead investigator Joanna Jen (University of California, Los Angeles, USA) and her colleagues sequenced all 28 exons and flanking introns of ROBO3 in ten HGPPS patients and identified ten different homozygous mutations scattered throughout the gene: one nonsense, one splice site, two frameshift, and six missense mutations. “The requirement that mutations be present on both alleles of ROBO3 for the manifestations of HGPPS to occur
328
suggests that the mutations cause loss of gene function”, say the authors. The researchers also did high resolution MRI studies in eight patients to characterise the neuroanatomical deficits. They found that the medulla was abnormally butterfly-shaped, with anterior flattening and an unusual midline cleft; abnormal flattening in the basis pontis was also seen, as was hypoplasia in the pontine tegmentum. Somatosensory and motor evoked potential studies in four patients showed abnormally reversed lateralisation of responses, indicating uncrossed ascending dorsal column medial-leminiscal sensory pathways and descending corticospinal pathways (Science; published online April 22, DOI: 10.1126/science.1096437). “It is simply amazing that the sensorimotor projections are uncrossed in HGPPS patients, who, remarkably, demonstrate no motor or sensory deficits”, says Jen, whose international network of clinicians have now identified ten con-
sanguineous families with HGPPS. “Furthermore, the brainstem appears malformed in HGPPS patients, indicating that aberrant crossing affects normal brainstem morphogenesis. ROBO3 is a member of the roundabout family of transmembrane receptors. Intriguingly, most robo proteins in mice and drosophila mediate midline repulsion of axons, rather than promoting midline crossing like ROBO3. However, the murine homologue to ROBO3 (Robo3) has recently been shown to promote midline crossing in mouse hindbrain and spinal cord (Cell 2004; 117: 157–69). Robo3 does this by acting upstream of Robo1 to prevent sensitivity of Robo1 to slits, which are midline repellents. “The most immediately apparent phenotype of the mutant embryos was the inability of their spinal cords to stay attached at the ventral midline when dissected , indicating a thinned or fragile floor plate”, say the authors of the Cell paper. James Butcher
THE LANCET Neurology Vol 3 June 2004
http://neurology.thelancet.com
For personal use. Only reproduce with permission The Lancet Publishing Group.