한빛사 논문
Muhammad Ansar 1, 21, Hyung-lok Chung 2, 3, 18, 21, Ali Al-Otaibi 4, Mohammad Nael Elagabani 5, 6, Thomas A. Ravenscroft 2, 3, Sohail A. Paracha 7, Ralf Scholz 8, Tayseer Abdel Magid 4, Muhammad T. Sarwar 7, Sayyed Fahim Shah 9, Azhar Ali Qaisar 10, Periklis Makrythanasis 1, 11, Paul C. Marcogliese 2, 3, Erik-Jan Kamsteeg 12, Emilie Falconnet 1, Emmanuelle Ranza 1, 13, 14, Federico A. Santoni 1, 15, Hesham Aldhalaan 16, Ali Al-Asmari 17, Eissa Ali Faqeih 17, Jawad Ahmed 7, Hans-Christian Kornau 5, 8, Hugo J. Bellen 2, 3, 18, 19, Stylianos E. Antonarakis 1, 13, 20
1 Department of Genetic Medicine and Development, University of Geneva, 1211 Geneva, Switzerland
2 Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
3 Jan and Dan Duncan Neurological Research Institute, Texas Children’s Hospital, Houston, TX 77030, USA
4 King Fahad Medical City, National Neuroscience Institute, 12231 Riyadh, Saudi Arabia
5 Neuroscience Research Center (NWFZ), Charité - Universitätsmedizin Berlin, 10117 Berlin, Germany
6 Freie Universität Berlin, Department of Biology, Chemistry, and Pharmacy, 14195 Berlin, Germany
7 Institute of Basic Medical Sciences, Khyber Medical University, 25100 Peshawar, Pakistan
8 Center for Molecular Neurobiology (ZMNH), University of Hamburg, 20251 Hamburg, Germany
9 Department of Medicine, KMU Institute of Medical Sciences, 26000 Kohat, Pakistan
10 Radiology department, Lady reading Hospital, 25000 Peshawar, Pakistan
11 Biomedical Research Foundation of the Academy of Athens, 115 27 Athens, Greece
12 Department of Human Genetics, Radboud University Medical Center, 6525 GA Nijmegen, the Netherlands
13 Service of Genetic Medicine, University Hospitals of Geneva, 1205 Geneva, Switzerland
14 Current address, Medigenome, The Swiss Institute of Genomic Medicine, 1207 Geneva, Switzerland
15 Department of Endocrinology Diabetes and Metabolism, University hospital of Lausanne, 1011 Lausanne, Switzerland
16 King Faisal Specialist Hospital & Research Centre, 12713 Riyadh, Saudi Arabia
17 Medical Genetics Department, Children’s Hospital, King Fahad Medical City, 12231 Riyadh, Saudi Arabia
18 Howard Hughes Medical Institute, Houston TX 77030, USA
19 Department of Neuroscience and Program in Developmental Biology, Baylor College of Medicine, Houston, TX 77030, USA
20 iGE3 Institute of Genetics and Genomics of Geneva, 1211 Geneva, Switzerland
21 These authors contributed equally to this work
Corresponding author : Hugo J. Bellen, Stylianos E. Antonarakis
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 2nd 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.
Keywords : autosomal recessive; Drosophila; schizo, mice; BRAG2; axon guidance; dendritic spines
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