Alternative titles; symbols
HGNC Approved Gene Symbol: NEMF
Cytogenetic location: 14q21.3 Genomic coordinates (GRCh38) : 14:49,782,083-49,852,788 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 14q21.3 | Intellectual developmental disorder with speech delay and axonal peripheral neuropathy | 619099 | Autosomal recessive | 3 |
The NEMF gene encodes a protein which acts as a 'rescue factor' to resolve stalled ribosomes that occur during translation. NEMF, known as Rqc2 in yeast, recognizes these aberrant stalled structures and facilitates the recruitment of the E3 ligase LTN1 (613083), which in turn ubiquitinates the nascent chain of incomplete peptides, leading to their proteasomal degradation. NEMF is part of the 'Ribosome-associated Quality Control' (RQC) complex (summary by Martin et al., 2020).
By SEREX (serologic analysis of recombinant cDNA expression libraries), Scanlan et al. (1998) cloned NEMF, which they called NY-CO-1, from a colon cancer cDNA library. The deduced 362-amino acid protein contains a nuclear targeting signal.
Ahmed et al. (2021) noted that NEMF is expressed in the human cerebral cortex, with enriched expression in excitatory neurons and weaker expression in inhibitory neurons. Expression was particularly strong in developing excitatory neurons, suggesting a role for this gene in early neurodevelopment.
By FISH, Carbonnelle et al. (1999) mapped the NEMF gene to chromosome 14q22.
In 8 patients from 6 unrelated families with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Martin et al. (2020) identified biallelic mutations in the NEMF gene (see, e.g., 608378.0001-608378.0003). The mutations were found by whole-exome or whole-genome sequencing and segregated with the disorder in all families; the patients were ascertained through the GeneMatcher program. Four consanguineous and 1 nonconsanguineous family carried nonsense or frameshift mutations, consistent with a loss-of-function effect. One patient from the sixth family carried compound heterozygous missense mutations. Functional studies of the mutations and studies of patient cells were not performed, but all were predicted to result in a loss of function. Martin et al. (2020) reported an additional patient (USA3) who carried a de novo heterozygous missense variant (I553T) that was not present in the gnomAD database. This individual developed an axonal sensorimotor peripheral neuropathy at 17 years of age; he also had mild speech delay and a tremor. Functional studies of this variant were not performed, but the authors postulated a dominant-negative effect that may have contributed to the phenotype. Detailed studies in mouse models with homozygous hypomorphic or loss-of-function mutations in the Nemf gene demonstrated an early-onset progressive neuromuscular disorder with motor impairment, gait difficulties, muscle wasting, defects at the neuromuscular junction, and distal axonal degeneration.
In 13 patients from 5 unrelated families with IDDSAPN, Ahmed et al. (2021) identified biallelic loss-of-function mutations in the NEMF gene (see, e.g., 608378.0004-608378.0006). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. The patients were gathered through the GeneMatcher program. Functional studies of the variants were not performed, but they were predicted to result in a loss of function: there were 2 frameshift and 2 splice site mutations. In vitro knockdown of the Nemf gene in mouse cortical neurons resulted in shorter axon length and shorter total neurite length compared to controls. There was also a decrease in overall dendritic spine density, an increase in immature thin spines, and decreased formation of excitatory and inhibitory synapses. These defects could be rescued by expression of wildtype human NEMF. Ahmed et al. (2021) postulated that disruption of the RQC complex due to NEMF mutations may render neurons more susceptible to degeneration and that disruption of NEMF may interrupt proper early neuronal development and synapse formation, causing both central and peripheral nervous system manifestations.
In a cohort of 337 patients with intellectual disability who underwent genetic studies, Anazi et al. (2017) identified 4 patients from 2 unrelated consanguineous families with homozygous frameshift mutations in the NEMF gene (see, e.g., 608378.0007). Functional studies of the variants were not performed, but both were predicted to result in a loss of function. All 4 affected children had impaired intellectual development with severe speech and language delay; additional clinical details were limited.
In a 7.5-year-old boy, born of consanguineous Syrian parents (family AUS1), with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Martin et al. (2020) identified a homozygous c.2608C-T transition in the NEMF gene, resulting in an arg870-to-ter (R870X) substitution. The mutation, which was found by whole-genome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 2 sibs, born of consanguineous Turkish parents (family DEU1), with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Martin et al. (2020) identified a homozygous c.2014A-T transversion in the NEMF gene, resulting in a lys672-to-ter (K672X) substitution. The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 2 brothers, born of consanguineous Saudi parents (family SAU1), with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Martin et al. (2020) identified a homozygous 5-bp duplication (c.2871_2875dupTGTAG) in the NEMF gene, resulting in a frameshift and premature termination (Asp959fsTer2). The mutation, which was found by whole-exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In 8 affected members of a highly consanguineous Pakistani family (family 1) with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Ahmed et al. (2021) identified a homozygous 1-bp deletion (c.2618del, NM_004713.6) in exon 26 of the NEMF gene, resulting in a frameshift and premature termination (Lys873ArgfsTer4). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The variant was not present in the gnomAD database. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a complete loss of NEMF function.
In 2 adult sibs, born of unrelated Slovenian parents (family 2), with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Ahmed et al. (2021) identified a homozygous A-to-C transversion in intron 9 of the NEMF gene (c.807-2A-C, NM_004713.6), resulting in a splicing defect. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Analysis of patient cells showed abnormal splicing with the deletion of exon 10. Additional studies of the variant were not performed, but it was predicted to result in a loss of function. The patients had progressive distal lower limb weakness and atrophy due to axonal peripheral neuropathy; one became wheelchair-dependent in the second decade. Other features included mildly impaired intellectual development, abnormal eye movement, and dysarthric speech.
In 2 unrelated patients, each born of consanguineous Saudi parents (families 4 and 5), with intellectual developmental disorder with speech delay and axonal peripheral neuropathy (IDDSAPN; 619099), Ahmed et al. (2021) identified a homozygous 1-bp insertion (c.1234_1235insC, NM_004713.6) in the NEMF gene, predicted to result in a frameshift and premature termination (Asn412ThrfsTer11). The mutations, which were found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the families. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function.
In a 7-year-old girl (patient 12DG0891), born of consanguineous parents, with intellectual developmental disorder with speech delay (see IDDSAPN, 619099), Anazi et al. (2017) identified a homozygous 1-bp insertion (c.1235_1236insC, NM_004713.4) in the NEMF gene, resulting in a frameshift and premature termination (Pro413SerfsTer10). The mutation, which was found by a combination of autozygosity mapping and exome sequencing, segregated with the disorder in the family. Functional studies of the variant and studies of patient cells were not performed, but the variant was predicted to result in a loss of function. Clinical details were limited. The proband was reported to have global developmental delay with severe speech and language impairment and microcephaly. Brain imaging did not show pathologic changes. Her similarly affected sister was also homozygous for the mutation.
Ahmed, A., Wang, M., Bergant, G., Maroofian, R., Zhao, R., Alfadhel, M., Nashabat, M., AlRifai, M. T., Eyaid, W., Alswaid, A., Beetz, C., Qin, Y., and 21 others. Biallelic loss-of-function variants in NEMF cause central nervous system impairment and axonal polyneuropathy. Hum. Genet. 140: 579-592, 2021. [PubMed: 33048237] [Full Text: https://doi.org/10.1007/s00439-020-02226-3]
Anazi, S., Maddirevula, S., Faqeih, E., Alsedairy, H., Alzahrani, F., Shamseldin, H. E., Patel, N., Hashem, M., Ibrahim, N., Abdulwahab, F., Ewida, N., Alsaif, H. S., and 36 others. Clinical genomics expands the morbid genome of intellectual disability and offers a high diagnostic yield. Molec. Psychiat. 22: 615-624, 2017. [PubMed: 27431290] [Full Text: https://doi.org/10.1038/mp.2016.113]
Carbonnelle, D., Liehr, T., Jacquot, C., Masson, D., Lustenberger, P., Denis, M. G., Roussakis, C. Assignment of the serologically defined colon cancer antigen 1 gene (SDCCAG1) to human chromosome band 14q22 by in situ hybridization. Cytogenet. Cell Genet. 86: 248-249, 1999. [PubMed: 10575219] [Full Text: https://doi.org/10.1159/000015352]
Martin, P. B., Kigoshi-Tansho, Y., Sher, R. B., Ravenscroft, G., Stauffer, J. E., Kumar, R., Yonashiro, R., Muller, T., Griffith, C., Allen, W., Pehlivan, D., Harel, T., and 16 others. NEMF mutations that impair ribosome-associated quality control are associated with neuromuscular disease. Nature Commun. 11: 4625, 2020. Note: Erratum: Nature Commun. 11: 5022, 2020. [PubMed: 32934225] [Full Text: https://doi.org/10.1038/s41467-020-18327-6]
Scanlan, M. J., Chen, Y.-T., Williamson, B., Gure, A. O., Stockert, E., Gordan, J. D., Tureci, O., Sahin, U., Pfreundschuh, M., Old, L. J. Characterization of human colon cancer antigens recognized by autologous antibodies. Int. J. Cancer 76: 652-658, 1998. [PubMed: 9610721] [Full Text: https://doi.org/10.1002/(sici)1097-0215(19980529)76:5<652::aid-ijc7>3.0.co;2-p]