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Developmental Biology - Brain Development
Identifying Gene Mutations In Intellectual Disability
Neurologic syndromes especially common in countries where marriage takes place between genetically related individuals, are now being identified more quickly...
It used to take several years or sometimes decades to unequivocally identify genes that cause rare syndromes affecting only a few individuals. Now, human geneticists and fly and mouse biologists working together with integrated data reveal a significantly accelerated pace of disease/gene discovery.
Although intellectual disability affects almost 200 million people around the globe, it remains misunderstood particularly in regards to the various underlying genes and/or molecular pathways involved. However, a new study from the laboratory of Hugo Bellen, in collaboration with Stylianos Antonarakis, professor emeritus at the University of Geneva, report their discovery of a new neurological syndrome. This syndrome appears especially common in countries where marriage between genetically related individuals, such as cousins, is common.
The research involved the detection of five affected individuals from two unrelated families in Pakistan and Saudi Arabia. All five of the patients had similar clinical symptoms - (1) intellectual disability, (2) developmental delays, (3) short stature, (4) speech loss, (5) low muscle tone, (6) aggressive behavior and sometimes (7) seizures. Analysis of these patients' exomes - which are all the protein coding regions of an individual's DNA - showed each patient carried mutations in the gene IQSEC1.
In humans, IQSEC1 belongs to a family of three related genes. Mutations in the other two gene family members, IQSEC2 and IQSEC3, had previously been implicated in other intellectual disabilities and/or seizures. This is the first study to identify mutations in IQSEC1 as cause of a neurodevelopmental disorder.
All five individuals in this small cohort are from consanguineous families and inherited two defective copies of IQSEC1, one from each parent. The defective copies of IQSEC1 identified in each patient produced altered proteins.
Unraveling How IQSEC1 Mutations Work
Researchers turned to fruit flies to investigate whether the IQSEC1 gene mutations caused intellectual disability and other symptoms in the five patients. First they genetically engineering flies to lack the schizo gene, which is equivalent to our human IQSEC1 gene. Then they tested whether human IQSEC1 could compensate for the loss of schizo.
"We found that normal versions of human IQSEC1 protein could partly function to compensate for the loss of schizo. But, the defective forms of IQSEC1 found in the (5) patients, could not. These findings are a strong indication that the patients' genetic variants produced non-functional IQSEC1 proteins."
Hugo J. Bellen PhD, Department of Molecular and Human Genetics, Baylor College of Medicine; Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital; Howard Hughes Medical Institute, Houston; and Department of Biology, Baylor College of Medicine, Houston, Texas, USA.
Furthermore, deletion of the schizo gene in flies resulted in dead fruit fly embryos with severe defects in neural projections and arborizations. Also their extensions of axons and dendrites, which provide structural connections between neighboring neurons, were severely disturbed.
Consistent with this finding, deletion of IQSEC1 from mice cortical neurons also led to similar defects in certain neural projections. Defective neuron branching impairs brain development and is implicated in several neurological conditions including intellectual disability, autism and seizures.
"The rise of research collaborative initiatives, such as the Undiagnosed Diseases Network, and the availability of new web tools such as GeneMatcher and MARRVEL, currently make it much easier for scientists to collaborate and, in significantly less time, solve rare medical mysteries."
Stylianos E. Antonarakis PhD, former Director of the Department of Genetic Medicine and Development, University of Geneva; Service of Genetic Medicine, University Hospitals of Geneva; iGE3 Institute of Genetics and Genomics of Geneva, Switzerland.
The work is published in the American Journal of Human Genetics.
Abstract
We report two consanguineous families with probands that exhibit intellectual disability, developmental delay, short stature, aphasia, and hypotonia in which homozygous non-synonymous variants were identified in IQSEC1 (GenBank: NM_001134382.3). In a Pakistani family, the IQSEC1 segregating variant is c.1028C>T (p.Thr343Met), while in a Saudi Arabian family the variant is c.962G>A (p.Arg321Gln). IQSEC1- 3 encode guanine nucleotide exchange factors for the small GTPase ARF6 and their loss affects a variety of actin-dependent cellular processes, including AMPA receptor trafficking at synapses. The ortholog of IQSECs in the fly is schizo and its loss affects growth cone guidance at the midline in the CNS, also an actin-dependent process. Overexpression of the reference IQSEC1 cDNA in wild-type flies is lethal, but overexpression of the two variant IQSEC1 cDNAs did not affect viability. Loss of schizo caused embryonic lethality that could be rescued to 2 nd instar larvae by moderate expression of the human reference cDNA. However, the p.Arg321Gln and p.Thr343Met variants failed to rescue embryonic lethality. These data indicate that the variants behave as loss-of-function mutations. We also show that schizo in photoreceptors is required for phototransduction. Finally, mice with a conditional Iqsec1 deletion in cortical neurons exhibited an increased density of dendritic spines with an immature morphology. The phenotypic similarity of the affecteds and the functional experiments in flies and mice indicate that IQSEC1 variants are the cause of a recessive disease with intellectual disability, developmental delay, and short stature, and that axonal guidance and dendritic projection defects as well as dendritic spine dysgenesis may underlie disease pathogenesis.
Authors
Muhammad Ansar, Hyung-lok Chung, Ali Al-Otaibi, Mohammad Nael Elagabani, Thomas A. Ravenscroft, Sohail A. Paracha, Ralf Scholz, Tayseer Abdel Magid, Muhammad T. Sarwar, Sayyed Fahim Shah, Azhar Ali Qaisar, Periklis Makrythanasis, Paul C. Marcogliese, Erik-Jan Kamsteeg, Emilie Falconnet, Emmanuelle Ranza, Federico A. Santoni, Hesham Aldhalaan, Ali Al-Asmari, Eissa Ali Faqeih, Jawad Ahmed, Hans-Christian Kornau, Hugo J. Bellen and Stylianos E. Antonarakis.
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Oct 30 2019 Fetal Timeline Maternal Timeline News
Fruit fly, mouse and human studies are collaborating to solve medical mysteries. CREDIT Baylor College of Medicine.
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