| *601023 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VALOSIN-CONTAINING PROTEIN; VCP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Alternative titles; symbols | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| CDC48, YEAST, HOMOLOG OF p97 | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HGNC Approved Gene Symbol: VCP | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cytogenetic location: 9p13.3 Genomic coordinates (GRCh37): 9:35,056,064 - 35,072,738 (from NCBI) | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Phenotype Relationships | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Description | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| The VCP gene encodes valosin-containing protein, a ubiquitously expressed multifunctional protein that is a member of the AAA+ (ATPase associated with various activities) protein family. It has been implicated in multiple cellular functions ranging from organelle biogenesis to ubiquitin-dependent protein degradation (summary by Weihl et al., 2009). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Cloning | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Clathrin is a structural protein found in coated pits and vesicles, organelles which are important in membrane trafficking functions such as endocytosis and Golgi sorting. A 100-kD protein, designated valosin-containing protein or VCP by early investigators, is a structural protein complexed with clathrin (see 118960). VCP is the homolog of yeast cdc48p, and is a member of a family that includes putative ATP-binding proteins involved in vesicle transport and fusion, 26S proteasome function, and assembly of peroxisomes (Pleasure et al., 1993). VCP was cloned from the pig (Koller and Brownstein, 1987) and mouse (Egerton et al., 1992). Druck et al. (1995) cloned a portion of the human cDNA. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Structure | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Johnson et al. (2010) noted that the VCP gene contains 17 exons. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Mapping | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Druck et al. (1995) used a partial human VCP cDNA to probe a panel of somatic cell hybrid DNAs and mapped the VCP gene to chromosome 9pter-q34. By database analysis, Hoyle et al. (1997) identified a human expressed sequence tag (EST) that shares 80% identity with the mouse 3-prime untranslated region. They designed primers to this EST and amplified and sequenced a 127-bp product from total human DNA. This product detected 1 fragment only in a HindIII digest of total human DNA, indicating there is only 1 VCP sequence in the human genome. Using the 127-bp sequence to screen a human PAC library, followed by FISH analysis, they mapped the VCP gene to chromosome 9p13-p12. They mapped the mouse Vcp gene to mouse chromosome 4 and found a probable pseudogene on the mouse X chromosome. The VCP gene maps to chromosome 9p13.3 (Johnson et al., 2010). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Gene Function | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Ye et al. (2001) demonstrated that VCP (CDC48 in yeast and p97 in mammals) is required for the export of endoplasmic reticulum (ER) into the cytosol. Whereas CDC48/p97 was known to function in a complex with the cofactor p47 in membrane fusion, Ye et al. (2001) demonstrated that its role in ER protein export requires the interacting partners UFD1 (601754) and NPL4 (606590). The AAA ATPase interacts with substrates at the ER membrane and is needed to release them as polyubiquitinated species into the cytosol. Zhang et al. (1999) created a substrate-trapping mutant of PTPH1 (176877) that interacted primarily with VCP in vitro but not in cells. A double mutant of PTPH1 had a marked reduction in phosphotyrosine content, specifically trapped VCP in vivo, and recognized the C-terminal tyrosines of VCP. Immunoblot analysis showed that wildtype PTPH1 specifically dephosphorylated VCP. Zhang et al. (1999) concluded that PTPH1 exerts its effects on cell growth through dephosphorylation of VCP and that tyrosine phosphorylation is an important regulator of VCP function. Watts et al. (2004) summarized that VCP has been associated with several essential cell protein pathways including cell cycle, homotypic membrane fusion, nuclear envelope reconstruction, postmitotic Golgi reassembly, DNA damage response, suppressor of apoptosis, and ubiquitin-dependent protein degradation. Higashiyama et al. (2002) identified a fruit fly VCP loss-of-function mutant as a dominant suppressor of expanded polyglutamine-induced neuronal degeneration. The suppressive effects of the loss-of-function mutant did not seem to result from inhibition of polyglutamine aggregate formation but rather from the degree of loss of VCP function. This suggested that a gene dosage response for VCP expression is essential to its function in expanded polyglutamine-induced neuronal degeneration. In support of this idea, transgenic fruit flies in which VCP levels were elevated experienced severe apoptotic cell death, whereas homozygous VCP loss-of-function mutants were embryonic lethal. Ye et al. (2004) found that VIMP (607918) recruits the p97 ATPase (VCP) and its cofactor, the UFD1/NPL4 complex, to the ER for retrotranslocation of misfolded proteins into the cytosol. They noted that all pathways of retrotranslocation appear to require the function of the p97 ATPase complex, which may provide the general driving force for the movement of proteins into the cytosol. Using a library of endoribonuclease-prepared short interfering RNAs (esiRNAs), Kittler et al. (2004) identified 37 genes required for cell division, one of which was VCP. These 37 genes included several splicing factors for which knockdown generates mitotic spindle defects. In addition, a putative nuclear-export terminator was found to speed up cell proliferation and mitotic progression after knockdown. Uchiyama et al. (2006) found that rodent p37 (610686) formed a complex with p97 in cytosol and localized to Golgi and ER. Small interfering RNA experiments in HeLa cells revealed that p37 was required for Golgi and ER biogenesis. Injection of anti-p37 antibodies into HeLa cells at different stages of the cell cycle showed that p37 was involved in Golgi and ER maintenance during interphase and in their reassembly at the end of mitosis. In an in vitro Golgi reassembly assay, the p97/p37 complex showed membrane fusion activity that required p115 (603344)-GM130 (GOLGA2; 602580) tethering and SNARE GS15 (BET1L). VCIP135 (VCPIP1) was also required, but its deubiquitinating activity was unnecessary for p97/p37-mediated activities. Ramadan et al. (2007) showed that p97 stimulates nucleus reformation by inactivating the chromatin-associated kinase Aurora B (604970). During mitosis, Aurora B inhibits nucleus reformation by preventing chromosome decondensation and formation of the nuclear envelope membrane. During exit from mitosis, p97 binds to Aurora B after its ubiquitylation and extracts it from chromatin. This leads to inactivation of Aurora B on chromatin, thus allowing chromatin decondensation and nuclear envelope formation. Ramadan et al. (2007) concluded that their data revealed an essential pathway that regulates reformation of the nucleus after mitosis and defined ubiquitin-dependent protein extraction as a common mechanism of Cdc48/p97 activity also during nucleus formation. Using human cell lines, Mueller et al. (2008) identified several components of a protein complex required for retrotranslocation or dislocation of misfolded proteins from the ER lumen to the cytosol for proteasome-dependent degradation. These included SEL1L (602329), HRD1 (SYVN1; 608046), derlin-2 (DERL2; 610304), the ATPase p97, PDI (P4HB; 176790), BIP (HSPA5; 138120), calnexin (CANX; 114217), AUP1 (602434), UBXD8 (FAF2), UBC6E (UBE2J1), and OS9 (609677). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Molecular Genetics | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Inclusion Body Myopathy With Paget Disease of Bone and Frontotemporal Dementia Watts et al. (2004) identified missense mutations in VCP as the cause of inclusion body myopathy with Paget disease of bone and frontotemporal dementia (IBMPFD; 167320). Ten of 13 families with this disorder had an amino acid change at arginine-155, either to histidine, proline, or cysteine. Arginine-155 of VCP was conserved in homologs through all species examined except in 2 C. elegans homologs, which had glutamine at that position. Arginine-191 was invariant in all species examined, and arginine-95 was substituted by histidine in only 2 species. Watts et al. (2004) suggested that since patients with IBMPFD are viable with relatively late onset of disease, the mutations identified do not disrupt the cell cycle or apoptosis pathways. They proposed that mutations in VCP cause Paget disease of bone by compromising ubiquitin binding and target similar cellular pathways or proteins. They suggested that the progressive neuronal degeneration has to do with protein quality control and ubiquitin protein degradation pathways. Finally, Watts et al. (2004) concluded that because IBMPFD is a dominant progressive syndrome, the mutations they identified are probably relatively subtle and aging, oxidative stress, and endoplasmic reticulum stress probably define a threshold at which the IBMPFD phenotype becomes manifest. In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with the mutant R155H (601023.0001) and R95G (601023.0004) proteins developed a prominent increase in diffuse and aggregated ubiquitin conjugates and showed impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. In human cells with IBMPFD-associated mutations, Ju et al. (2008) found that treatment with a proteasome inhibitor resulted in increased cell death and an increase in perinuclear ubiquitinated proteins, but no clear aggresomes, compared to wildtype. Expression of an aggregate protein in mutant cells did not result in proper formation of inclusion bodies or aggresomes. A similar lack of inclusion body formation was observed in mutant mouse muscle fibers in vivo. Further studies showed that mutant VCP trapped aggregated proteins but failed to release them to aggresomes or inclusion bodies. This was reversed upon coexpression with HDAC6 (300272), a VCP-binding protein that facilitates formation of aggresomes. Ju et al. (2008) concluded that mutations in the VCP gene impaired the proper clearance of aggregated proteins. Amyotrophic Lateral Sclerosis 14, With or Without Frontotemporal Dementia Using exome sequencing, Johnson et al. (2010) identified a heterozygous mutation in the VCP gene (R191Q; 601023.0006) in 4 affected members of an Italian family with amyotrophic lateral sclerosis-14 (ALS14; 613954) with or without frontotemporal dementia. Screening of the VCP gene in 210 familial ALS cases and 78 autopsy-proven ALS cases identified 3 additional pathogenic VCP mutations (601023.0001; 601012.0008, and 601023.0009) in 4 patients. The findings expanded the phenotype associated with VCP mutations to include classic ALS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Animal Model | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Weihl et al. (2007) found that transgenic mice overexpressing the R155H mutation became progressively weaker in a dose-dependent manner starting at 6 months of age. There was abnormal muscle pathology, with coarse internal architecture, vacuolation, and disorganized membrane morphology with reduced caveolin-3 (CAV3; 601253) expression at the sarcolemma. Even before animals displayed measurable weakness, there was an increase in ubiquitin-containing protein inclusions and high molecular weight ubiquitinated proteins. These findings suggested a dysregulation in protein degradation. Custer et al. (2010) developed and characterized transgenic mice with ubiquitous expression of wildtype and disease-causing versions of human VCP/p97. Mice expressing VCP/p97 harboring the mutations R155H (601023.0001) or A232E (601023.0003) exhibited progressive muscle weakness, and developed inclusion body myopathy including rimmed vacuoles and TDP43 (605078) pathology. The brain showed widespread TDP43 pathology, and the skeleton exhibited severe osteopenia accompanied by focal lytic and sclerotic lesions in vertebrae and femur. In vitro studies indicated that mutant VCP caused inappropriate activation of the NF-kappa-B (see 164011) signaling cascade, which could contribute to the mechanism of pathogenesis in multiple tissues including muscle, bone, and brain. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| ALLELIC VARIANTS (Selected Examples): | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Table View | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0001 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG155HIS [dbSNP:rs121909329] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 7 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a G-to-A transition at nucleotide 464 of the VCP gene, resulting in an arg155-to-his substitution (R155H). This mutation appears to have arisen independently on several haplotype backgrounds. Viassolo et al. (2008) identified heterozygosity for the R155H mutation in 3 affected members of an Italian family with IBMPFD. All 3 had progressive inclusion body myopathy and rapidly progressive severe dementia, but only 1 developed Paget disease. In vitro functional expression studies by Weihl et al. (2006) showed that R155H-mutant protein properly assembled into a hexameric structure and showed normal ATPase activity. Cell transfected with the mutant protein showed a prominent increase in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. Johnson et al. (2010) identified heterozygosity for the R155H mutation, which they stated resulted from an 853G-A transition in exon 5, in a member of the family reported by Watts et al. (2004). However, the family member reported by Johnson et al. (2010) had classic ALS (ALS14; 613954) without evidence of Paget disease, myopathy, or frontotemporal dementia. Postmortem examination of this patient showed loss of brainstem and spinal cord motor neurons with Bunina bodies in surviving neurons, TDP43 (TARDBP; 605078)-positive immunostaining, and mild pallor of the lateral descending corticospinal tracts, all features consistent with diagnosis of ALS. The findings expanded the phenotype associated with VCP mutations, even within a single family. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0002 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG155CYS [dbSNP:rs121909330] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 2 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a C-to-T transition at nucleotide 463 of the VCP gene, resulting in an arg155-to-cys substitution (R155C). Kim et al. (2011) identified a heterozygous R155C mutation in 3 Korean sibs with IBMPFD. The proband developed progressive dementia presenting as fluent aphasia and language difficulties with onset at age 47. She never developed myopathy, but did develop asymptomatic Paget disease with increased serum alkaline phosphatase and lytic bone lesions on imaging. Her brother developed slowly progressive proximal muscle weakness at age 50, followed by frontotemporal dementia characterized initially by comprehension defects at age 54. He never had Paget disease, although serum alkaline phosphatase was increased. A second brother developed muscle weakness at age 47, followed by Paget disease at age 53, and dementia at age 61. Brain MRI in all patients showed asymmetric atrophy in the anterior inferior and lateral temporal lobes and inferior parietal lobule with ventricular dilatation on the affected side (2 on the left, 1 on the right). Two had glucose hypometabolism in the lateral temporal and inferior parietal areas, with less involvement of the anterior temporal and frontal lobes compared to those with typical semantic dementia. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0003 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ALA232GLU [dbSNP:rs121909331] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a C-to-A transversion at nucleotide 695 of the VCP gene, resulting in an ala-to-glu change at codon 232 (A232E). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0004 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG95GLY [dbSNP:rs121909332] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a C-to-G transversion at nucleotide 283 of the VCP gene, resulting in an arg-to-gly substitution at codon 95 (R95G). In vitro functional expression studies by Weihl et al. (2006) showed that cells transfected with R95G-mutant protein developed a prominent increased in diffuse and aggregated ubiquitin conjugates and impaired function of endoplasmic reticulum-associated degradation (ERAD), as well as a distorted ER structure. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0005 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG155PRO [dbSNP:rs121909333] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 464 of the VCP gene, resulting in an arg-to-pro substitution at codon 155 (R155P). This family was originally reported by Tucker et al. (1982). | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0006 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA, INCLUDED | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG191GLN [dbSNP:rs121909334] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 1 of 13 families with autosomal dominant IBMPFD (167320), Watts et al. (2004) identified a G-to-C transversion at nucleotide 572 of the VCP gene, resulting in an arg-to-gln substitution at codon 191 (R191Q). Using exome sequencing, Johnson et al. (2010) identified heterozygosity for the R191Q mutation in the VCP gene, which they stated resulted from a 961G-A transition in exon 5, in 4 affected members of an Italian family with amyotrophic lateral sclerosis-14 (ALS14; 613954). Affected individuals presented in adulthood with limb-onset motor neuron symptoms that rapidly progressed to involve all 4 limbs and the bulbar musculature, consistent with a classical ALS phenotype. All patients had unequivocal upper and lower motor signs, and none had evidence of Paget disease. One patient showed mild frontotemporal dementia. Autopsy material was not available. A parent of the proband had died at age 58 with dementia, parkinsonism, Paget disease, and upper limb weakness, suggesting IBMPFD. The findings indicated an expanded phenotypic spectrum for VCP mutations. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0007 INCLUSION BODY MYOPATHY WITH EARLY-ONSET PAGET DISEASE AND FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG159HIS [dbSNP:rs121909335] | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In 4 affected sibs of an Austrian family with autosomal dominant inclusion body myopathy and Paget disease but without dementia (167320), Haubenberger et al. (2005) identified a heterozygous 688G-A transition in exon 5 of the VCP gene, resulting in an arg159-to-his (R159H) substitution. The mutation occurred in a highly conserved region close to the codon 155 hotspot described by Watts et al. (2004) and was not present in 384 control chromosomes. None of the 4 affected sibs demonstrated frontotemporal dementia even though all were over 60 years of age. Haubenberger et al. (2005) noted that only approximately 30% of patients with VCP mutations develop dementia, illustrating phenotypic variability. In a follow-up of this family, van der Zee et al. (2009) noted that 1 patient had developed dementia at age 64. Van der Zee et al. (2009) also identified the R159H mutation in affected members of 2 unrelated Belgian families. In 1 family, patients presented with frontotemporal lobar degeneration only, whereas in the other family, patients developed frontotemporal lobar degeneration, Paget disease of the bone, or both without signs of inclusion body myopathy for any of the mutation carriers. Haplotype analysis showed that the 2 families and the Austrian family reported by Haubenberger et al. (2005) were unrelated. Autopsy data of 3 patients from the 2 Belgian families showed frontotemporal lobar degeneration with numerous ubiquitin-immunoreactive, intranuclear inclusions and dystrophic neurites staining positive for TDP43 (TARDBP; 605078) protein. Van der Zee et al. (2009) commented on the high degree of clinical heterogeneity and incomplete penetrance of the disorder in different families carrying the same mutation. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0008 AMYOTROPHIC LATERAL SCLEROSIS 14 WITH OR WITHOUT FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ARG159GLY | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In affected members of a family with ALS14 with or without frontotemporal dementia (613954), Johnson et al. (2010) identified a heterozygous 864C-G transversion in exon 5 of the VCP gene, resulting in an arg159-to-gly (R159G) substitution in a conserved residue. The mutation was not found in 3,138 control chromosomes, and a different pathogenic mutation had previously been reported in this codon (R159H; 601023.0007). Two patients had classic ALS with frontotemporal dementia, and a third obligate mutation carrier had Paget disease, followed by ALS without cognitive impairment. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| .0009 AMYOTROPHIC LATERAL SCLEROSIS 14 WITHOUT FRONTOTEMPORAL DEMENTIA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| VCP, ASP592ASN | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| In a patient with ALS14 without frontotemporal dementia (613954), Johnson et al. (2010) identified a heterozygous 2163G-A transition in exon 14 of the VCP gene, resulting in an asp592-to-asn (D592N) substitution in a residue directly adjacent to the central pore formed by the VCP hexamer. The mutation was not found in 3,138 control chromosomes. A maternal uncle had previously been diagnosed with ALS. | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| REFERENCES | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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