Intro arrow 11. Genetic Etiology arrow 11.1 Genetic
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11. Genetic Etiology
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11.1 Genetic Etiology

Dyslexia is a specific difficulty with learning to read,in the absence of sensory or neurological impairments and despite an appropriate social, intellectual and educational environment. While the neurological and cognitive basis of dyslexia has yet to be elucidated, the strong genetic etiology of this disorder is widely accepted. Dyslexia is highly familial and heritable, and most likely results from interactions between multiple genetic and environmental risk factors.

 In 1979, Albert Galaburda and Thomas Kemper examined a brain removed during an autopsy from a 20-year-old man with dyslexia and reported that there were nerve cells in unusual parts of the cerebral cortex. Subsequent studies at the Dyslexia Research Laboratory at Beth Israel Hospital in Boston, MA, of four dyslexic males and three dyslexic females showed that in the males (less so in females) clusters of "ectopic" neurons are consistently seen in the outside layer of the cerebral neocortex.

This layer usually is devoid of nerve cell bodies. Most ectopias were in the frontal and perisylvian language regions. Ectopias are produced before six months of gestation when there is a breach in the pial-glial border which normally prevents neurons from migrating too far.

 Scientists recently identified a risk haplotype (a genetic constitution of an individual chromosome) associated with dyslexia on chromosome 6p22.2 which spans the TTRAP gene and portions of THEM2 and KIAA0319. In the presence of the risk haplotype, the expression of the KIAA0319 gene is reduced but the expression of the other two genes remains unaffected. Using in situ hybridization, they detect a very distinct expression pattern of the KIAA0319 gene in the developing cerebral neocortex of mouse and human fetuses. Moreover, interference with rat Kiaa0319 expression in utero leads to impaired neuronal migration in the developing cerebral neocortex. These data suggest a direct link between a specific genetic background and a biological mechanism leading to the development of dyslexia: the risk haplotype on chromosome 6p22.2 down-regulates the KIAA0319 gene which is required for neuronal migration during the formation of the cerebral neocortex. Source

 Interference with KIAA0319 disrupts radial migration in the developing rat neocortex.

A. Depiction of in utero electroporation assay for neuronal migration in fetal neocortex. Combinations of plasmids coding for shRNAs, eGFP, and KIAA0319 were injected into the ventricles of the E14 rat forebrain, in order to transfect neuronal progenitor cells at the ventricular zone (VZ) surface. Over the course of four days, neurons migrated radially towards the intermediate zone (IZ) and cortical plate (CP).

B. Average distance migrated by neurons 4 days following co-transfection of eGFP and one the following five plasmids:

i. KIAA0319shRNA

ii. shRNA containing scrambled sequence of a KIAA0319shRNA vector

iii. KIAA0319shRNA co-transfected with a KIAA0319 expression plasmid (rescue experiment)



C-G. Images showing positions of populations of transfected neurons with one of the five plasmid combinations, as described above.

H. Relationship between radial glial fibers in the IZ labelled with an antibody to nestin (red) and cells transfected with eGFP and KIAA0319shRNA. The inset at the bottom right corner shows typical parallel arrangements between migrating neurons and radial glial fibers. Scale bars: 150 μm in C-G, and 15 μm in H.

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