Alternative titles; symbols
HGNC Approved Gene Symbol: ERMARD
Cytogenetic location: 6q27 Genomic coordinates (GRCh38): 6:169,751,306-169,781,600 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 6q27 | ?Periventricular nodular heterotopia 6 | 615544 | Autosomal dominant | 3 |
By searching for genes within the 1.2-Mb minimal critical deleted region in chromosome 6q for isolated periventricular nodular heterotopia (PVNH6; 615544), Conti et al. (2013) identified ERMARD, which they called C6ORF70. The predicted full-length protein (GenBank NM_018341.1) contains 678 amino acids. RT-PCR of adult and fetal human brain total RNA revealed ERMARD splice variants that use alternative ATG codons and encode deduced proteins of 552 and 509 amino acids. Both of these isoforms have 2 transmembrane domains near the C terminus. Epitope-tagged ERMARD localized in a punctate distribution in transfected HEK293T cells, and these puncta mainly colocalized with the endoplasmic reticulum.
Conti et al. (2013) determined that the ERMARD gene contains 18 exons. Exons 1, 4, and 6 contain ATG codons.
By genomic sequence analysis, Conti et al. (2013) mapped the ERMARD gene to chromosome 6q27.
By array CGH of 155 patients with brain malformations, Conti et al. (2013) identified 12 patients with heterozygous deletions of chromosome 6q27 involving the ERMARD gene. Eight of the deletions occurred de novo, and 2 were inherited from an affected parent. The size of the deletions varied, but all shared a common 1.2-Mb deleted region containing 4 known genes (DLL1, 606582; PHF10, 613069; TCTE3, 186977; and THBS2, 188061) and 2 predicted genes (ERMARD and WDR27). Developmental brain abnormalities were variable and included periventricular nodular heterotopia, hypoplastic corpus callosum, colpocephaly, polymicrogyria, under-rotated or hypoplastic hippocampi, and cerebellar hypoplasia. Associated clinical manifestations included epilepsy (9/12), developmental delay (12/12), ataxic or clumsy gait (6/12), and facial dysmorphism (11/12).
In a girl with periventricular nodular heterotopia-6 (PVNH6; 615544) manifest as delayed psychomotor development and seizures, Conti et al. (2013) identified a de novo heterozygous missense mutation in the ERMARD gene (I250N; 615532.0001). The mutation was found by whole-exome sequencing of 14 patients with isolated bilateral PVNH who did not carry copy number variations. Direct sequencing of the ERMARD gene in 50 patients with PVNH did not identify any mutations, suggesting that mutations in this gene may be a rare cause of the disorder.
Using in utero electroporation, Conti et al. (2013) demonstrated that knockdown of C6orf70 in developing rat brain caused a massive neuronal migration defect, significant arrest of cells within the ventricular zone, and development of heterotopic nodules along the walls of the lateral ventricles. Coexpression of human C6ORF70, which was resistant to the C6orf70 knockdown construct, prevented migration arrest in the ventricular zone.
In a girl with periventricular nodular heterotopia-6 (PVNH6; 615544), Conti et al. (2013) identified a de novo heterozygous T-to-A transversion in exon 12 of the ERMARD gene. This change corresponded to a c.752T-A transversion resulting in an ile250-to-asn (I250N) substitution in the long isoform and a c.622T-A transversion resulting in an ile207-to-asn (I207N) substitution in the short isoform. Both substitutions occurred at highly conserved residues. The mutation was found by whole-exome sequencing of 14 unrelated patients with isolated bilateral PVNH who did not carry copy number variations. The mutation was confirmed by Sanger sequencing; it was not found in the Kaviar2 database. Expression of the mutant protein in HEK293 cells resulted in a predominantly dispersed pattern of staining, suggesting that the mutation alters the subcellular localization. Western blot analysis showed markedly reduced mutant protein levels compared to wildtype (58% reduction for the longer isoform and 12% reduction for the shorter isoform).
Conti, V., Carabalona, A., Pallesi-Pocachard, E., Parrini, E., Leventer, R. J., Buhler, E., McGillivray, G., Michel, F. J., Striano, P., Mei, D., Watrin, F., Lise, S., and 14 others. Periventricular heterotopia in 6q terminal deletion syndrome: role of the C6orf70 gene. Brain 136: 3378-3394, 2013. [PubMed: 24056535] [Full Text: https://doi.org/10.1093/brain/awt249]