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HGNC Approved Gene Symbol: EMC10
Cytogenetic location: 19q13.33 Genomic coordinates (GRCh38) : 19:50,476,507-50,490,871 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 19q13.33 | Neurodevelopmental disorder with dysmorphic facies and variable seizures | 619264 | Autosomal recessive | 3 |
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).
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.
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.
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.
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.
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.
Kaiyrzhanov et al. (2022) identified homozygous mutations in the EMC10 gene in 10 patients from 6 unrelated consanguineous families. Five of the mutations were novel (614545.0003-614545.0007) and one was previously identified (614545.0002). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the families. The mutations were either absent or present at a rare allelic frequency in multiple public and private variant databases.
Mice carrying a hemizygous 1.3-Mb chromosomal deficiency on chromosome 16 (Df(16)A +/- mice; see 609030), which is syntenic to the human 1.5-Mb 22q11.2 microdeletion associated with risk of schizophrenia (SCZD; 181500), have primary cognitive and behavioral deficits related to SCZD due to abnormal processing and levels of brain microRNAs, particularly Mir185 (615576). Diamantopoulou et al. (2017) demonstrated that upregulated levels of Emc10, a target of Mir185, in postnatal brain was a significant contributor to the SCZD phenotype in Df(16)A +/- mice. Genetic normalization of Emc10 levels in Df(16)A +/- mice prevented key SCZ-related deficits in prepulse inhibition, working memory-dependent learning, and social memory, but it failed to rescue hyperactivity and fear memory deficits. Furthermore, Emc10 knockout and overexpression had dissociable effects on cognition and behavior of mice. Mechanistically, reduction of Emc10 levels in Df(16)A +/- mice rescued synaptic plasticity deficits in the prefrontal cortex (PFC) and prevented structural alterations in the PFC.
Zhou et al. (2018) found that Emc10 -/- mice had normal survival rate, appearance, and gross behavior compared with wildtype. However, Emc10 -/- males were completely infertile, and females exhibited reduced fertility, as deletion of Emc10 affected interaction of spermatozoa with oocytes. Loss of Emc10 did not affect spermatogenesis or influence development of testis and epididymis, but it impaired sperm function, as Emc10 was involved sperm maturation in the epididymis and maintenance of normal sperm morphology during transit through the epididymis. Mechanistically, Emc10 deletion dramatically altered the proteomic expression profile in spermatozoa. In particular, loss of Emc10 resulted in inactivation of Na/K-ATPase (see 182310), leading to ion imbalance in spermatozoa. Analysis of semen from asthenozoospermic patients revealed that EMC10 was involved in regulation of human sperm motility, and that low sperm EMC10 was a causative factor for human male infertility.
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.
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.
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.
In a Bedouin girl (patient S8) born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for the c.287delG mutation in the EMC10 gene. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In an Azerbaijani boy (patient S1), born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for a 1-bp duplication (c.543dup, NM_206538.4) in the EMC10 gene, resulting in a frameshift and premature termination (Asn182GlnfsTer16). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In Bukharan Jewish brothers (patients S2 and S3), born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for a 1-bp deletion (c.66delC, NM_206538.4) in the EMC10 gene, resulting in a frameshift and premature termination (Ser23ValfsTer82). The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In 3 Egyptian sisters (patients S4-S6), born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for a c.259C-T transition (c.259C-T, NM_206538.4) in the EMC10 gene, resulting in a gln87-to-ter (Q87X) substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In a Persian girl (patient S7), born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for a c.289C-T transition (c.289C-T, NM_206538.4) in the EMC10 gene, resulting in an arg97-to-ter (R97X) substitution. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
In Egyptian sisters (patient S9 and S10), born to consanguineous parents, Kaiyrzhanov et al. (2022) identified homozygosity for a c.188-2A-C transversion (c.188-2A-C, NM_206538.4) in intron 2 of the EMC10 gene, resulting in a splicing abnormality. The mutation, which was identified by whole-exome sequencing, was present in heterozygous state in the parents. Functional studies were not performed.
Diamantopoulou, A., Sun, Z., Mukai, J., Xu, B., Fenelon, K., Karayiorgou, M., Gogos, J. A. Loss-of-function mutation in Mirta22/Emc10 rescues specific schizophrenia-related phenotypes in a mouse model of the 22q11.2 deletion. Proc. Nat. Acad. Sci. 114: E6127-E6136, 2017. [PubMed: 28696314] [Full Text: https://doi.org/10.1073/pnas.1615719114]
Junes-Gill, K. S., Gallaher, T. K., Gluzman-Poltorak, Z., Miller, J. D., Wheeler, C. J., Fan, X., Basile, L. A. hHSS1: a novel secreted factor suppressor of glioma growth located at chromosome 19q13.33. J. Neurooncol. 102: 197-211, 2011. [PubMed: 20680400] [Full Text: https://doi.org/10.1007/s11060-010-0314-6]
Kaiyrzhanov, R., Rocca, C., Suri, M., Gulieva, S., Zaki, M. S., Henig, N. Z., Siquier, K., Guliyeva, U., Mounir, S. M., Marom, D., Allahverdiyeva, A., Megahed, H., and 13 others. Biallelic loss of EMC10 leads to mild to severe intellectual disability. Ann. Clin. Transl. Neurol. 9: 1080-1089, 2022. [PubMed: 35684946] [Full Text: https://doi.org/10.1002/acn3.51602]
Shao, D. D., Straussberg, R., Ahmed, H., Khan, A., Tian, S., Hill, R. S., Smith, R. S., Majmundar, A. J., Ameziane, N., Neil, J. E., Yang, E., Al Tenaiji, A., and 21 others. A recurrent, homozygous EMC10 frameshift variant is associated with a syndrome of developmental delay with variable seizures and dysmorphic features. Genet. Med. 23: 1158-1162, 2021. [PubMed: 33531666] [Full Text: https://doi.org/10.1038/s41436-021-01097-x]
Umair, M., Ballow, M., Asiri, A., Alyafee, Y., Al Tuwaijri, A., Alhamoudi, KM., Aloraini, T., Abdelhakim, M., Althagafi, A. T., Kafkas, S., Alsubaie, L., Alrifai, M. T., Hoehndorf, R., Alfares, A., Alfadhel, M. EMC10 homozygous variant identified in a family with global developmental delay, mild intellectual disability, and speech delay. Clin. Genet. 98: 555-561, 2020. [PubMed: 32869858] [Full Text: https://doi.org/10.1111/cge.13842]
Zhou, Y., Wu, F., Zhang, M., Xiong, Z., Yin, Q., Ru, Y., Shi, H., Li, J., Mao, S., Li, Y., Cao, X., Hu, R., Liew, C. W., Ding, Q., Wang, X., Zhang, Y. EMC10 governs male fertility via maintaining sperm ion balance. J. Molec. Cell Biol. 10: 503-514, 2018. [PubMed: 29659949] [Full Text: https://doi.org/10.1093/jmcb/mjy024]