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FUS

From SNPedia
is agene
is mentioned by
Full namefused in sarcoma
EntrezGene2521
PheGenI2521
VariationViewer2521
ClinVarFUS
GeneCardsFUS
dbSNP2521
DiseasesFUS
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wikipediaFUS
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UniProtP35637
EnsemblENSG00000089280
OMIM137070
# SNPs24
 Max MagnitudeChromosome positionSummary
rs1052352031,183,958
rs1085308015031,191,407
rs121909667031,191,408
rs121909668031,191,418
rs121909669031,191,410
rs121909670031,191,418
rs121909671031,191,419
rs186547381031,190,398
rs267606831031,191,089
rs267606832031,185,061
rs267606833031,191,427
rs376510148031,191,486
rs387906627031,191,052
rs387906628031,185,031
rs387907274031,189,158
rs559575844031,191,548
rs741810031,182,621
rs752076094031,185,175
rs780606789031,191,546
rs886041389031,191,429
rs886041390031,191,431
rs886041577031,191,073
rs886041776031,191,083
rs929867031,180,161


FUS gene and ALS

AMYOTROPHIC LATERAL SCLEROSIS 6

OMIM 137070

Amyotrophic Lateral Sclerosis 6

Lattante et al. (2013) provided a review of FUS mutations associated with amyotrophic lateral sclerosis (ALS6; 608030). FUS mutations occur in about 5% of patients with familial ALS and in 1% of patients with sporadic disease.

.0001 AMYOTROPHIC LATERAL SCLEROSIS 6, AUTOSOMAL RECESSIVE

FUS, HIS517GLN rs121909667

In 4 affected members of a consanguineous family with amyotrophic lateral sclerosis-6 (ALS6; 608030), Kwiatkowski et al. (2009) identified a homozygous 1551C-G transversion in exon 15 of the FUS gene, resulting in a his517-to-gln (H517Q) substitution. The family originated from Cape Verde, a small island off the western coast of Africa. Three asymptomatic family members were also homozygous for the mutation, but all were younger than the mean age at disease onset of 45 years. The mutation was not detected in 1,446 control DNA samples from North America; 1 heterozygote was observed in 132 chromosomes from Cape Verde.


.0002 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG521GLY rs121909668 (same as .0004, see below)

.0003 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG518LYS rs121909669

In affected members of a family with amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1553G-A transition in exon 15 of the FUS gene, resulting in an arg518-to-lys (R518K) substitution. Inheritance was autosomal dominant, and the mean age at onset was 40.3 years. The mutation was not found in 1,446 control DNA samples.


.0004 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG521CYS rs121909668

In affected members of 3 unrelated families with amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1561C-T transition in exon 15 of the FUS gene, resulting in an arg521-to-cys (R521C) in the C-terminal domain. The mutation was not found in 1,446 control DNA samples.

Vance et al. (2009) identified a heterozygous R521C mutation in 6 affected members of a British family with ALS6 (Ruddy et al., 2003) and in 3 affected members of an additional family with ALS and in 3 index ALS cases.

Corrado et al. (2010) identified a heterozygous R521C mutation in 2 unrelated Italian patients with ALS6. One had a family history of the disorder, and the other had sporadic disease. Onset occurred at age 34 and 54 years, respectively, and both had an unusual phenotype with proximal, mostly symmetric upper limb weakness with neck and axial involvement.

Millecamps et al. (2010) identified heterozygosity for the R521C mutation in 3 of 162 French probands with familial ALS. One patient was also heterozygous for a mutation in the ANG gene (K17I; 105850.0002), which causes ALS9 (611895),

Yan et al. (2010) identified heterozygosity for the R521C mutation in 6 families with ALS6: 4 were Caucasian, 1 was African American, and 1 was Chinese. Five families had classic ALS6. The proband in the remaining family had ALS, her brother had parkinsonism and dementia, and her mother and sister had dementia. These features expanded the phenotype associated with FUS mutations.


.0005 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG521HIS rs121909671

In affected members of a family with autosomal dominant amyotrophic lateral sclerosis (ALS6; 608030), Kwiatkowski et al. (2009) identified a heterozygous 1562G-A transition in exon 15 of the FUS gene, resulting in an arg521-to-his (R521H) substitution. The mutation was not found in 1,446 control DNA samples.

Vance et al. (2009) identified a heterozygous R521H substitution in affected members of 2 families with ALS6 and 1 index case.


.0006 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, GLY507ASP rs267606831

In 2 unrelated Italian patients with sporadic amyotrophic lateral sclerosis (ALS6; 608030), Corrado et al. (2010) identified a heterozygous 1520G-A transition in exon 14 of the FUS gene, resulting in a gly507-to-asp (G507D) substitution in a conserved residue. The mutation was not found in 500 healthy controls.

Hewitt et al. (2010) identified a heterozygous G507D mutation in a U.K. man with predominantly lower motor neuron ALS involving both the lower and upper limbs. He had no family history of neurologic disease, had onset at age 69 years, and died of respiratory failure 42 months after symptom onset. Postmortem examination showed marked loss of lower motor neurons at all spinal levels and neuronal and glial cytoplasmic inclusions, which stained for FUS.


.0007 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA TREMOR, HEREDITARY ESSENTIAL, 4, INCLUDED

FUS, ARG216CYS rs267606832

In 1 of 1,009 Italian patients with amyotrophic lateral sclerosis (ALS6; 608030), Corrado et al. (2010) identified a heterozygous 646C-T transition in exon 6 of the FUS gene, resulting in an arg216-to-cys (R216C) substitution in a conserved residue. The mutation was not found in 793 controls.

In 2 of 270 unrelated patients with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous R216C substitution at a highly conserved residue in the glycine-rich domain. The mutation was found in 1 (0.1%) of 900 control alleles. One of the patients had a family history of the disorder, but family members were not available for study. The mutation disrupts a CpG site, which may cause an epigenetic effect on gene expression through changes in methylation. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS due to FUS mutations. In addition, ETM4 cells with the R216C mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin.


.0008 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG524TRP rs267606833

In 3 U.K. patients, including 2 sibs, with amyotrophic lateral sclerosis (ALS6; 608030), Hewitt et al. (2010) identified a heterozygous 1570A-T transversion in exon 15 of the FUS gene, resulting in an arg524-to-trp (R524W) substitution. The mutation was not found in 293 controls. One of the patients had onset of a progressive muscular atrophy variant of motor neuron disease with upper limb onset at the age of 61 years. His brother presented with a similar pattern of disease at age 58, but DNA was not available. Postmortem examination of the first patient showed marked depletion of lower motor neurons with glial cytoplasmic and nuclear inclusions that stained for p62 (SQSTM1; 601530). There was FUS staining predominantly in the nucleus of neurons and glia, with some lower motor neurons showing strong cytoplasmic FUS expression. An affected brother and sister with the R524W mutation had classic limb-onset ALS.


.0009 AMYOTROPHIC LATERAL SCLEROSIS 6 WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, ARG495TER rs387906627

In 3 affected members of a German family with amyotrophic lateral sclerosis (ALS6; 608030), Waibel et al. (2010) identified a heterozygous 1483C-T transition in exon 14 of the FUS gene, resulting in an arg495-to-ter (R495X) substitution predicted to produced a truncated protein lacking the nuclear localization sequence. The age at onset ranged from 31 to 36 years, with rapid disease progression leading to death 12 to 18 months later. All presented with bulbar signs and symptoms and had predominantly lower motor signs. None had dementia.

Yan et al. (2010) identified heterozygosity for the R495X mutation in a Caucasian family with ALS6. There was wide phenotypic variability: the age at onset ranged from 24 to 44 years in 4 mutation carriers, and 2 mutation carriers were unaffected at age 57 and 61 years, respectively. One mutation carrier had onset at age 14 years, and postmortem analysis was consistent with Fazio-Londe disease (211500).

Bosco et al. (2010) reported a 5-generation family with 8 affected members with early-onset ALS caused by the R495X mutation, which led to a relatively severe ALS clinical phenotype compared with FUS missense mutations. Expression of R495X FUS, which abrogates a putative nuclear localization signal at the C terminus of FUS, in HEK-293 cells and in the zebrafish spinal cord caused a striking cytoplasmic accumulation of the protein to a greater extent than that observed for recessive (H517Q; 137070.0001) and dominant (R521G; 137070.0002) missense mutants. In response to oxidative stress or heat-shock conditions in cultures and in vivo, the ALS-linked FUS mutants, but not wildtype FUS, assembled into perinuclear stress granules in proportion to their cytoplasmic expression levels. The authors proposed a potential link between FUS mutations and cellular pathways involved in stress responses that may be relevant to altered motor neuron homeostasis in ALS.


.0010 AMYOTROPHIC LATERAL SCLEROSIS 6 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA

FUS, GLY206SER rs387906628

In a family of South Korean origin with amyotrophic lateral sclerosis (ALS6; 608030), Yan et al. (2010) identified a heterozygous 616G-A transition in exon 6 of the FUS gene, resulting in a gly206-to-ser (G206S) substitution. The proband developed ALS at age 54 years, and his 2 brothers had behavior problems in their forties consistent with frontotemporal dementia.


.0011 TREMOR, HEREDITARY ESSENTIAL, 4

FUS, GLN290TER rs387907274

In affected members of a large family with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous 868C-T transition in exon 9 of the FUS gene, resulting in a gln290-to-ter (Q290X) substitution in the nuclear export signal motif. The mutation segregated with the disorder in all patients who were determined to be 'definitely' or 'probably' affected. However, only 54% of those who were 'possibly' affected carried the mutation, and 1 unaffected individual who was 24 years old also carried the mutation. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was not found in 450 controls or in a large exome database. Studies of patient lymphoblastoid cells showed that the mutant mRNA was degraded by nonsense-mediated mRNA decay, resulting in haploinsufficiency. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. None of the patients over the age of onset of amyotrophic lateral sclerosis had signs of that disorder.


.0012 TREMOR, HEREDITARY ESSENTIAL, 4

FUS, PRO431LEU rs186547381

In a patient with hereditary essential tremor-4 (ETM4; 614782), Merner et al. (2012) identified a heterozygous 1292C-T transition in exon 12 of the FUS gene, resulting in a pro431-to-leu (P431L) substitution at a highly conserved residue in the zinc finger domain. The patient had a family history of the disorder, but family members were not available for analysis. The mutation was not found in 450 controls. Although the mutation occurred in the last nucleotide of exon 12, no splicing abnormalities were detected. ETM4 patient lymphoblastoid cells showed significantly lower overall expression of mutant FUS mRNA than did cells from patients with ALS6 due to FUS mutations. In addition, ETM4 cells with the P431L mutation showed a significant increase in FUS mRNA expression after treatment with the translation inhibitor puromycin.

Reference https://omim.org/entry/137070