Intellectual disability syndromic and non-syndromic
Gene: NEMF

NEMF (nuclear export mediator factor)
EnsemblGeneIds (GRCh38): ENSG00000165525
EnsemblGeneIds (GRCh37): ENSG00000165525
OMIM: 608378, Gene2Phenotype
NEMF is in 3 panels

2 reviews

Konstantinos Varvagiannis (Other)

Green List (high evidence)

Biallelic (and possibly monoallelic) pathogenic variants in this gene are associated with DD/ID.

Martin et al (2020 - PMID:32934225) report on 8 individuals from 6 families with a juvenile neuromuscular disease due to biallelic NEMF variants. (In one of these 8 cases it could not be ruled out that a de novo and maternally inherited variant were on the same allele, as phase was not determined). A ninth individual with similar presentation was found to harbor a single NEMF missense SNV as de novo event (due to a speculated dominant-negative effect). This individual had a similar presentation.

Features incl. hypotonia (4/8 with biallelic variant (B) | 1/1 monoallelic (M) ), DD/ID (7/8B | 0/1M) with speech delay as universal feature (8/8B | 1/1M), axonal neuropathy (3/3B | 1/1M), ataxia (3/8B | 0/1M). Other findings included tremor (1/7B | 1/1M), abnormal brain imaging (2/6B / ?/1M), kyphosis/scoliosis (4/8B | 0/1M), respiratory distress (1/8B | 0/1M).

NEMF (Rqc2 in yeast) encodes the nuclear export mediator factor, a component of the Ribosome-associated Quality Control (RCQ) complex which is involved in proteolytic targeting of incomplete polypeptides produced by ribosome stalling. NEMF facilitates the recruitment of E3 ligase Listerin (LTN1) which ubiquitinates nascent polypeptide chains for subsequent proteasomal degradation.

The author provide evidence that mice homozygous for Nemf missense mutations display progressive motor phenotypes, exhibit neurogenic atrophy and progressive axonal degeneration. A further NEMF-null mouse model displayed more severe phenotype (with heterozygous mice being unaffected).

Equivalent mutations (of those in the above mouse model) in yeast (Rqc2) were shown to interfere with its ability to modify aberrant translation products with C-terminal tails which assist RQC-mediated protein degradation.

Mutation of Ltn1 (belonging to the same protein control pathway) has been also shown to lead to neurodegeneration in mice.

Overall NEMF is thought to play a role in neuronal translational homeostasis and the disorder to be mediated by dysfunction of the RQC pathway (normally protecting neurons against degeneration).
Created: 3 Oct 2020, 8:27 p.m. | Last Modified: 3 Oct 2020, 8:32 p.m.

Panel Version: 0.3053

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Publications

32934225

Created: 3 Oct 2020, 8:27 p.m.
Last Modified: 3 Oct 2020, 8:32 p.m.
Panel version: 0.3053

Zornitza Stark (Victorian Clinical Genetics Services; Australian Genomics)

Green List (high evidence)

Nine individuals from 7 unrelated families reported with a mixed CNS/PNS phenotype. 7/9 had ID, 4/9 had formal assessments demonstrating axonal neuropathy, 3/9 had ataxia; muscular atrophy, hypotonia, respiratory distress, scoliosis also described in some. Three independently generated mouse models had progressive motor neuron degeneration.
Sources: Literature
Created: 18 Sep 2020, 10:44 p.m.

Mode of inheritance
BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Phenotypes
Intellectual developmental disorder with speech delay and axonal peripheral neuropathy, MIM# 619099; Intellectual disability; neuropathy

Publications

32934225

Created: 18 Sep 2020, 10:44 p.m.

Panel version: 0.3198

Details

Mode of Inheritance

BOTH monoallelic and biallelic, autosomal or pseudoautosomal

Sources

Expert Review Green
Literature

Phenotypes

Intellectual developmental disorder with speech delay and axonal peripheral neuropathy, MIM# 619099
Intellectual disability
neuropathy

OMIM

608378

Clinvar variants

Variants in NEMF

Penetrance

None

Publications

32934225

Panels with this gene