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ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 10; EMC10

ENDOPLASMIC RETICULUM MEMBRANE PROTEIN COMPLEX, SUBUNIT 10; EMC10

Alternative titles; symbolsER MEMBRANE PROTEIN COMPLEX, SUBUNIT 10CHROMOSOME 19 OPEN READING FRAME 63; C19ORF63Other entities represented in this entry:HEMATOPOI...

Alternative titles; symbols

  • ER MEMBRANE PROTEIN COMPLEX, SUBUNIT 10
  • CHROMOSOME 19 OPEN READING FRAME 63; C19ORF63

Other entities represented in this entry:

  • HEMATOPOIETIC SIGNAL PEPTIDE-CONTAINING SECRETED PROTEIN 1, INCLUDED; HSS1, INCLUDED
  • HEMATOPOIETIC SIGNAL PEPTIDE- AND MEMBRANE DOMAIN-CONTAINING PROTEIN 1, INCLUDED; HSM1, INCLUDED

HGNC Approved Gene Symbol: EMC10

Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38): 19:50,476,482-50,505,904 (from NCBI)

▼ Description
The EMC10 gene encodes one of 10 components of the endoplasmic reticulum complex (EMC), which is a highly conserved protein complex related to membrane protein biology (summary by Shao et al., 2021).

▼ Cloning and Expression
Using microarray analysis to identify genes differentially expressed in mouse hematopoietic stem cells, followed by database analysis and PCR of mouse and human cDNA libraries, Junes-Gill et al. (2011) cloned 2 splice variants of mouse and human C19ORF63, which they called HSM1 and HSS1. The deduced 262- and 254-amino acid human HSM1 and HSS1 proteins are identical for the first 227 amino acids, including an N-terminal signal sequence, an N-glycosylation site, and an O-glycosylation site. HSM1, but not HSS1, has a transmembrane domain near its C terminus. The mouse and human HSS1 proteins share about 86% identity. Qualitative PCR detected HSS1 expression in several brain regions, with highest expression in pituitary. Western blot analysis detected secretion of HSS1 from transfected 293T cells. HSS1 had an apparent molecular mass of 30 kD, larger than the predicted molecular mass of 24.2 kD for mature HSS1. Nuclear staining was also observed in transfected U87 human glioblastoma cells. Database analysis revealed orthologs of C19ORF63 in mammals, invertebrates, and plants.

Shao et al. (2021) found expression of EMC10 in human infant brain. EMC10 colocalized with MAP2 (157130), a nonnuclear protein expressed in mature neurons. NeuN (616999), a nuclear marker of mature neurons, also showed colocalization with EMC10.

▼ Gene Function
The A172 and U87 human glioblastoma cell lines have deletions in a region of chromosome 9 corresponding to the C19ORF63 locus. Using RT-PCR, Junes-Gill et al. (2011) confirmed that neither cell line expressed HSS1 or HSM1. Transfection of HSS1 partly restored contact inhibition and reduced aggregation of U87 cells. It also suppressed the malignant phenotype of U87 cells in vitro and following injection into immunocompromised mice. Similarly, expression of HSS1 reduced the rate of growth and colony formation in A172 cells. HSS1 expression in U87 cells altered the gene expression profile. Apelin (300297) was one of the most downregulated genes, and ADAMTS1 (605174) and SIK1 (SNF1LK; 605705) were among the upregulated genes.

▼ Gene Structure
Junes-Gill et al. (2011) determined that the C19ORF63 gene contains 8 exons and spans at least 6.8 kb. Exon 7, which is alternatively spliced, and exon 8 contain stop codons.

▼ Mapping
By genomic sequence analysis, Junes-Gill et al. (2011) mapped the C19ORF63 gene to chromosome 19q13.33. They mapped the mouse ortholog to chromosome 7.

▼ Molecular Genetics
In 2 sibs, born of consanguineous Arab parents, with neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS; 619264), Umair et al. (2020) identified a homozygous splice site mutation in the EMC10 gene (614545.0001). The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR analysis of patient cells showed decreased EMC10 mRNA levels compared to controls.

In 12 patients from 7 unrelated consanguineous families of Middle Eastern descent with NEDDFAS, Shao et al. (2021) identified a homozygous frameshift mutation in the EMA10 gene (614545.0002). The mutation, which was found by whole-exome or whole-genome sequencing at various centers, was confirmed by Sanger sequencing and segregated with the disorder in the families. It was not present in the homozygous state in public databases. Studies of cells derived from some patients and in vitro studies showed that the mutant protein was unstable due to proteasomal degradation. Shao et al. (2021) concluded that the mutation resulted in a loss of EMC10 function, which may have detrimental effects on transmembrane protein dynamics in various cell types.

▼ Animal Model
Shao et al. (2021) noted that Emc10-null mice exhibit neurologic and behavioral abnormalities, including abnormal vocalization, gait, activity, and anxiety-related mannerisms as well as defects in cognitive processes, such as memory and learning.

▼ ALLELIC VARIANTS ( 2 Selected Examples):

.0001 NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND VARIABLE SEIZURES
EMC10, IVS6AS, G-A, -1
In 2 sibs, born of consanguineous Arab parents, with neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS; 619264), Umair et al. (2020) identified a homozygous G-to-A transition in intron 6 of the EMC10 gene (c.679-1G-A, NM_206538.4), predicted to result in a splice site alteration. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. RT-PCR analysis of patient cells showed decreased EMC10 mRNA levels compared to controls.

.0002 NEURODEVELOPMENTAL DISORDER WITH DYSMORPHIC FACIES AND VARIABLE SEIZURES
EMC10, 1-BP DEL, 287G
In 12 patients from 7 unrelated consanguineous families of Middle Eastern descent with neurodevelopmental disorder with dysmorphic facies and variable seizures (NEDDFAS; 619264), Shao et al. (2021) identified a homozygous 1-bp deletion (c.287delG, NM_206538.3) in the EMA10 gene, predicted to result in a frameshift and premature termination (Gly96AlafsTer9). The mutation, which was found by whole-exome or whole-genome sequencing at various centers, was confirmed by Sanger sequencing and segregated with the disorder in the families. It was not present in the homozygous state in public databases. Haplotype analysis identified 2 distinct haplotypes among the families, suggesting that the mutation occurred in a hotspot; the deletion was within a homopolymeric repeat sequence that predisposes to DNA replication errors. Studies of cells derived from some patients showed reduced but not absent EMC10 expression, suggesting that the mutation results in an unstable protein. The mutations resulted in a putative truncated protein of 103 amino acids in length and was predicted to abolish the C-terminal region that interacts with core EMC proteins. In vitro functional expression studies in HeLa cells transfected with the mutation showed that the mutant protein was unstable due to proteasomal degradation. Shao et al. (2021) concluded that the mutation resulted in a loss of EMC10 function, which may have detrimental effects on transmembrane protein dynamics in various cell types.

Tags: 19q13.33