Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature.

Détails

ID Serval
serval:BIB_8CED6D5E768A
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Institution
Titre
Bi-allelic Variants in IQSEC1 Cause Intellectual Disability, Developmental Delay, and Short Stature.
Périodique
American journal of human genetics
Auteur(s)
Ansar M., Chung H.L., Al-Otaibi A., Elagabani M.N., Ravenscroft T.A., Paracha S.A., Scholz R., Abdel Magid T., Sarwar M.T., Shah S.F., Qaisar A.A., Makrythanasis P., Marcogliese P.C., Kamsteeg E.J., Falconnet E., Ranza E., Santoni F.A., Aldhalaan H., Al-Asmari A., Faqeih E.A., Ahmed J., Kornau H.C., Bellen H.J., Antonarakis S.E.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Statut éditorial
Publié
Date de publication
07/11/2019
Peer-reviewed
Oui
Volume
105
Numéro
5
Pages
907-920
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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 <sup>nd</sup> 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.
Mots-clé
Adult, Alleles, Animals, Child, Dendritic Spines/genetics, Developmental Disabilities/genetics, Drosophila/genetics, Dwarfism/genetics, Female, Guanine Nucleotide Exchange Factors/genetics, Humans, Intellectual Disability/genetics, Male, Mice, Mutation/genetics, Saudi Arabia, Synapses/genetics, Young Adult, BRAG2, Drosophila, autosomal recessive, axon guidance, dendritic spines, schizo, mice
Pubmed
Web of science
Création de la notice
15/10/2019 14:08
Dernière modification de la notice
27/04/2020 6:20
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