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IMMEDIATE-EARLY RESPONSE 3-INTERACTING PROTEIN 1; IER3IP1

IMMEDIATE-EARLY RESPONSE 3-INTERACTING PROTEIN 1; IER3IP1

HGNC Approved Gene Symbol: IER3IP1Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:47,152,833-47,176,363 (from NCBI)▼ Cloning and ExpressionBy ...

HGNC Approved Gene Symbol: IER3IP1

Cytogenetic location: 18q21.1 Genomic coordinates (GRCh38): 18:47,152,833-47,176,363 (from NCBI)

▼ Cloning and Expression
By large-scale partial sequencing of a human liver cDNA library and EST database searching, Yiu et al. (2004) identified a novel cDNA encoding a deduced 82-amino acid protein, which they designated immediate-early response-3-interacting protein-1 (IER3IP1). IER3IP1 contains a putative G-patch domain and 2 transmembrane domains. Northern blot analysis revealed a single 1.5-kb transcript expressed at high levels in heart, skeletal muscle, and kidney, moderate levels in liver and brain, and low levels in placenta, lung, and peripheral blood leukocytes. Yiu et al. (2004) found that the IER3IP1 protein localizes to the endoplasmic reticulum through its C-terminal transmembrane domain.

▼ Gene Structure
Yiu et al. (2004) demonstrated that the IER3IP1 gene contains 3 exons.

▼ Mapping
By somatic cell hybrid analysis, Yiu et al. (2004) mapped the IER3IP1 gene to chromosome 18. They refined the mapping to 18q12 by radiation hybrid analysis.

Gross (2016) mapped the IER3IP1 gene to chromosome 18q21.1 based on an alignment of the IER3IP1 sequence (GenBank AF164798) with the genomic sequence (GRCh38).

▼ Gene Function
In cultured fibroblasts, Poulton et al. (2011) demonstrated that expression of IER3IP1 was increased approximately 1.5-fold by TNF-alpha (191160).

Using CRISPR-lineage tracing at cellular resolution in heterogeneous tissue (CRISPR-LICHT), which enabled parallel loss-of-function studies in human cerebral organoid tissue, Esk et al. (2020) tested 173 microcephaly candidate genes and found that 25, including IER3IP1, were involved in microcephaly-associated pathways. Characterization of IER3IP1 showed that it regulated endoplasmic reticulum function and extracellular matrix protein secretion crucial for tissue integrity, dysregulation of which resulted in microcephaly.

▼ Molecular Genetics
By homozygosity mapping followed by candidate gene sequencing in 2 consanguineous families with microcephaly, epilepsy, and diabetes syndrome-1 (MEDS1; 614231), Poulton et al. (2011) identified different homozygous mutations in the IER3IP1 gene: V21G (609382.0001) and L78P (609382.0002). Poulton et al. (2011) concluded that the disorder was due to abnormally increased apoptosis.

In 4 patients from 2 unrelated consanguineous Egyptian families with MEDS1, Abdel-Salam et al. (2012) identified homozygosity for the L78P mutation in the IER3IP1 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed.

In a boy with MEDS1, Shalev et al. (2014) identified compound heterozygous mutations in the IER3IP1 gene: V21G and c.79delT (609382.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. The V21G mutation was inherited from the unaffected father, who was of mixed Libyan-Tangier origin, whereas the c.79delT mutation was inherited from the unaffected mother, who was of mixed Ashkenazi Jewish/Spanish/French origin. Functional studies of the variants were not performed.

▼ ALLELIC VARIANTS ( 3 Selected Examples):

.0001 MICROCEPHALY, EPILEPSY, AND DIABETES SYNDROME 1
IER3IP1, VAL21GLY
In a patient with microcephaly, epilepsy, and diabetes syndrome-1 (MEDS1; 614231), who was born of consanguineous parents of Moroccan origin, Poulton et al. (2011) identified a homozygous 62T-G transversion in exon 1 of the IER3IP1 gene, resulting in a val21-to-gly (V21G) substitution at a highly conserved residue in the first hydrophobic domain predicted to be a signal sequence for targeting to the endoplasmic reticulum. Each unaffected parent was heterozygous for the mutation, which was not found in 300 control chromosomes. Patient fibroblasts showed an increased tendency to undergo apoptosis after stress induction. Similar results were obtained in control cells after knockdown of IER3IP1, suggesting that IER3IP1 is needed to protect cells from stress. The patient had originally been reported by de Wit et al. (2006), and died at age 18 months.

In a boy with MEDS1, Shalev et al. (2014) identified compound heterozygous mutations in the IER3IP1 gene: an A-to-C transversion (chr18.44,704,487A-C, GRCh37), resulting in a V21G substitution, and a 1-bp deletion (c.79delT; 609382.0003), resulting in a frameshift and premature termination (Phe27fsSerTer25). The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, were filtered against the 1000 Genomes Project and Exome Sequencing Project databases, and segregated with the disorder in the family. The V21G mutation was inherited from the unaffected father, who was of mixed Libyan-Tangier origin, whereas the c.79delT mutation was inherited from the unaffected mother, who was of mixed Ashkenazi Jewish/Spanish/French origin. Functional studies of the variants were not performed.

.0002 MICROCEPHALY, EPILEPSY, AND DIABETES SYNDROME 1
IER3IP1, LEU78PRO
In a patient with microcephaly, epilepsy, and diabetes syndrome-1 (MEDS1; 614231), who was born of consanguineous parents in Argentina, Poulton et al. (2011) identified a homozygous 233T-C transition in exon 3 of the IER3IP1 gene, resulting in a leu78-to-pro (L78P) substitution at a highly conserved residue in the second hydrophobic transmembrane domain. Each unaffected parent was heterozygous for the mutation, which was not found in 300 control chromosomes.

In 4 patients from 2 unrelated consanguineous Egyptian families with MEDS1, Abdel-Salam et al. (2012) identified a homozygous L78P mutation in the IER3IP1 gene. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the families. Functional studies of the variant were not performed.

.0003 MICROCEPHALY, EPILEPSY, AND DIABETES SYNDROME 1
IER3IP1, 1-BP DEL, 79T
For discussion of the c.79delT mutation (chr18.44,702,569delA, GRCh37) in the IER3IP1 gene that was found in compound heterozygous state in a patient with microcephaly, epilepsy, and diabetes syndrome-1 (MEDS1; 614231) by Shalev et al. (2014), see 609382.0001.

Tags: 18q21.1