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How gene mutation causes higher intelligence

summary: A new study suggests that a rare genetic mutation that causes blindness is also linked to above-average intelligence.

source: University of Leipzig

Synapses are the contact points in the brain through which neurons “talk” to each other. Disruptions in this connection lead to diseases of the nervous system, since altered synaptic proteins, for example, can impair this complex molecular mechanism. This can lead to mild symptoms, but also very severe disabilities in those affected.

It intrigued neurobiologists Professor Tobias Langenhan and Professor Manfred Heckmann, from Leipzig and Würzburg respectively, when they read in a scientific publication about a mutation that destroys a synaptic protein.

At first, the affected patients attracted the attention of scientists because the mutation blinded them. However, the doctors then noted that the patients also had above-average intelligence.

“It is very rare for a mutation to lead to improvement rather than loss of function,” says Langenhan, professor and chair holder at the Rudolf Schönheimer Institute of Biochemistry in the School of Medicine.

Two neurobiologists from Leipzig and Würzburg have been using fruit flies to analyze synaptic functions for many years.

“Our research project was designed to introduce patients’ mutation to the corresponding gene in the fly and use techniques such as electrophysiology to test what happens next to the synapses. Our assumption was that the mutation makes patients very smart because it improves communication between neurons that includes the affected protein,” explains Langenhan.

Of course, you cannot perform these measurements on synapses in the brains of human patients. You have to use animal models for that.”

“75 percent of the genes that cause disease in humans are also found in fruit flies.”

First, the scientists, along with researchers from Oxford, showed that a fly protein called RIM appeared to be molecularly identical to the human protein. This was necessary in order to be able to study changes in the human brain in the fly. In the next step, neurobiologists inserted mutations into the fly’s genome that looked exactly as they did to infected people. Then they took electrophysiological measurements of the synaptic activity.

“We have already observed that animals with the mutation showed increased transmission of information at their synapses. Professor Langenhan concludes that this striking effect on the fly’s synapses can be found in the same or similar manner in human patients, and could explain their increased cognitive performance, as well as their blindness.”

The scientists also discovered how increased transmission occurs at synapses: the molecular components of a transmitting neuron that stimulate synaptic impulses converge together as a result of the effect of the mutation and lead to an increased release of neurotransmitters. The new method, super-resolution microscopy, was one of the techniques used in the study.

The scientists also discovered how increased transmission occurs at synapses: the molecular components of a transmitting neuron that stimulate synaptic impulses converge together as a result of the effect of the mutation and lead to an increased release of neurotransmitters. The image is in the public domain

Professor Langenhan, who also assisted the study, says Professor Hartmut Schmidt’s research group of the Karl Ludwig Institute in Leipzig.

The project beautifully demonstrates how an unusual animal model such as the fruit fly can be used to gain a very deep understanding of the diseases of the human brain. Animals are genetically very similar to humans. It is estimated that 75 percent of the genes involved in diseases in humans are also found in Drosophila,” explains Professor Langenhan, pointing to further research on the topic at the Faculty of Medicine:

“We have started several joint projects with human geneticists, pathologists and the Center for Integrated Research and Therapy (IFB) AdiposityDiseases team; Based at the University Hospital Leipzig, they study developmental brain disorders, the development of malignancies and obesity. Here also, we will introduce disease-causing mutations into Drosophila to replicate and better understand human disease. “

About this genetics and intelligence research news

author: Susan Hoster
source: University of Leipzig
Contact: Susan Hoster – University of Leipzig
picture: The image is in the public domain

original search: Access closed.
“Human cognition-promoting CORD7 mutation increases active region number and synaptic release” by Tobias Langenhan et al. brain


a summary

The human cognition-enhancing CORD7 mutation increases active region number and synaptic release

see also

This is a schematic diagram of the study

Humans who carry the CORD7 mutation (cone dystrophy 7) have both verbal IQ and working memory. This chromosomal dominant syndrome is caused by the exchange of the mono-amino acid R844H (human numbering) present in 310 The snail from C.2A domain of RIMS1/RIM1 (Rab3 interacting molecule 1).

RIM is an evolutionarily conserved multidomain protein and an essential component of presynaptic active regions, which are centrally involved in rapid, Ca2+The release of an excitatory neurotransmitter. How the CORD7 mutation affects synaptic function has remained unclear until now.

Here we created Drosophila black belly As a disease model to elucidate the effects of CORD7 mutation on RIM function and synaptic vesicle release.

To this end, using protein expression and X-ray crystallography, we have solved the molecular structure of fruit fly c2A domain with a resolution of 1.92 and in comparison with its mammalian counterpart confirmed that the CORD7 mutation site is structurally conserved in the fly RIM.

Furthermore, CRISPR/Cas9-assisted genomic engineering has been used to generate edge Exchange alleles encoding R915H CORD7 or variants R915E, R916E (flight numbering) to cause local charge reversal at 310 snail.

By characterizing the electrophysiology by bipolar voltage clamp and confocal recordings, we determined that the CORD7 mutation exerts a quasi-dominant rather than a dominant effect on synaptic transmission resulting in faster and more efficient synaptic release and increased volume of the readily releasing pool but decreased sensitivity to BAPTA’s fast calcium chelator.

In addition, the edge The CORD7 allele increased the number of active presynaptic regions but left their nanoscale organization unconcerned as indicated by ultra-resolution microscopy of the presynaptic scaffold protein Bruchpilot/ELKS/CAST.

We conclude that the CORD7 mutation leads to tighter release coupling, increased size of the easily releasing pool and more release sites, thus promoting more efficient synaptic transmitter release.

These results strongly suggest that similar mechanisms may underlie the CORD7 disease phenotype in patients and that enhanced synaptic transmission may contribute to their increased cognitive abilities.

2022-05-10 17:41:08

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