This report describes an intellectual developmental disorder with short stature and behavioral abnormalities (IDDSSBA), which shows autosomal recessive inheritance. The human gene implicated in this disease is IQSEC1, a G-protein that is a member of the ADP-ribosylation factor (Arf) family. There is a single high-ranking ortholog of IQSEC1 in Drosophila, siz, for which multiple genetic reagents, including RNAi targeting constructs, misexpression element constructs, and other alleles caused by insertional mutagenesis, have been generated.
The human gene Hsap\IQSEC1 has been introduced into flies, both as wild-type and as variant alleles associated with IDDSSBA. See the 'Disease-Implicated Variants' table below. Strong expression of Hsap\IQSEC1 is lethal in Drosophila, but flies expressing either of the Hsap\IQSEC1 mutant forms are viable. Moderate expression of wild-type human Hsap\IQSEC1 in embryonic lethal Dmel\siz mutants allows them to survive until second instar larval stage, indicating that Hsap\IQSEC1 is capable of partial functional complementation (heterologous rescue) of siz. Neither of the mutant forms tested are capable of rescuing siz mutants.
In Drosophila, siz is expressed in the nervous system, including both neurons and glia, and mutants show defects in axonal guidance, dendritic projection, and commissural anatomy. Insertion alleles causing truncation of all siz transcripts are embryonic lethal, and flies lacking siz activity in the eye have severely impaired vision or none at all.
[updated Apr. 2022 by FlyBase; FBrf0222196]
[INTELLECTUAL DEVELOPMENTAL DISORDER WITH SHORT STATURE AND BEHAVIORAL ABNORMALITIES; IDDSSBA](https://omim.org/entry/618687)
[IQ MOTIF- AND SEC7 DOMAIN-CONTAINING PROTEIN 1; IQSEC1](https://omim.org/entry/610166)
Affected individuals from two families carrying different homozygous mutations in IQSEC1 shared similar clinical features, including intellectual disability, developmental delay, short stature, hypotonia, and aphasia. Individuals carrying the c.962G>A (p.Arg321Gln) variant also had early onset epileptic seizures, whereas individuals carrying the c.1028C >T (p.Thr343Met) variant did not. (Adapted from Ansar et al. 2019, FBrf0243929.)
As reported by Ansar et al. 2019 (FBrf0243929): Two sibs in family 1, of Pakistani descent, had global developmental delay with delayed motor milestones, severely impaired intellectual development, and aphasia. Other features included short stature, small head circumference, facial dysmorphism, and aggressive behavior. Two brothers in family 2 developed refractory seizures at about 2 months of age. Seizure types included febrile, generalized tonic-clonic, and absence, with frequent episodes of status epilepticus. They had global developmental delay with severely impaired intellectual development, but were able to walk independently at age 3 and had a few words at age 4. Other features included short stature, hypotonia, ataxic gait, and behavioral abnormalities, including inattention, hyperactivity, and aggression. [from MIM:618687, 2020.01.06]
In affected individuals from 2 unrelated consanguineous families with IDDSSBA, Ansar et al. 2019 (FBrf0243929) identified homozygous missense mutations in the IQSEC1 gene (T343M, 610166.0001 and R321Q, 610166.0002). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. [from MIM:618687, 2020.01.06]
The IQSec family of proteins, based on the presence of a characteristic calmodulin-binding IQ motif and the conserved catalytic domain referred to as the Sec7 domain, are a sub-family of Arf (ADP-ribosylation factor) GEFs (guanine nucleotide exchange factor). The non-canonical IQ motif in the IQSec family preferentially binds calcium-free calmodulin, and releases it upon calcium binding. (Adapted from D'Souza and Casanova 2016 and references therein; pubmed:27739918.)
Many to one: three human genes to one Drosophila gene.
Many to one: three human genes to one Drosophila gene.
Many to one: three human genes to one Drosophila gene.
Single, high-ranking ortholog of human IQSEC1. siz is also orthologous to two other human paralogs of IQSEC1, named IQSEC2 and IQSEC3.
