Alternative titles; symbols
HGNC Approved Gene Symbol: SQSTM1
Cytogenetic location: 5q35.3 Genomic coordinates (GRCh38): 5:179,806,393-179,838,078 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 5q35.3 | Frontotemporal dementia and/or amyotrophic lateral sclerosis 3 | 616437 | Autosomal dominant | 3 |
| Myopathy, distal, with rimmed vacuoles | 617158 | Autosomal dominant | 3 | |
| Neurodegeneration with ataxia, dystonia, and gaze palsy, childhood-onset | 617145 | Autosomal recessive | 3 | |
| Paget disease of bone 3 | 167250 | Autosomal dominant | 3 |
The SQSTM1 gene encodes a scaffolding protein that regulates a variety of biologic processes, including NFKB1 (164011) signaling, apoptosis, transcription regulation, and ubiquitin-mediated autophagy (review by Rea et al., 2014).
The Src homology type 2 (SH2) domain is a highly conserved motif of about 100 amino acids which mediates protein-protein interactions by binding to phosphotyrosine. p56-lck (153390), a T-cell-specific src family tyrosine kinase with an SH2 domain, is involved in T-cell signal transduction. A 62-kD protein (p62) was identified by Park et al. (1995) as a ligand of the p56-lck SH2 domain.
Joung et al. (1996) cloned the gene for p62 by purifying the p62 protein to obtain peptide microsequences, producing a PCR product with degenerate oligonucleotides, and then using this PCR product to screen a HeLa cell cDNA library. Sequence analysis of full-length cDNAs by Joung et al. (1996) revealed that the p62 gene encodes a 440-amino acid polypeptide with the following conserved domains: (1) a cysteine-rich domain, predicted to be a metal-binding site involved in protein-protein or protein-DNA interaction; (2) a region with homology to the cdc42 GTPase binding-site; and (3) a PEST motif which is a degradation signal found in many short-lived proteins. Northern blot analysis suggested that p62 is expressed ubiquitously in all tissues examined.
Gong et al. (1999) screened a yeast 2-hybrid library made from rat hippocampal mRNA against full-length Kv-beta-2 (601142). Two previously unknown interacting proteins were identified, one of which was identical to Zip (PKC-zeta (176982)-interacting protein), the rat homolog of p62. Zip1 and Zip2, which arise from alternative splicing, are identical except for 27 residues missing from Zip2.
Park et al. (1995) found that the p56-lck SH2 domain binds to p62 at the ser59 of p62 only when that serine is phosphorylated. Moreover, Park et al. (1995) found that p62 is associated with a serine/threonine kinase activity and also binds to ras GTP-ase-activating protein, a negative regulator of the ras signaling pathway.
Joung et al. (1996) expressed epitope-tagged p62 in HeLa cells and showed that the expressed protein bound to the lck SH2 domain and that this binding was dependent on the N-terminal 50 amino acids of p62 but not on the tyrosine residue in this region. Thus Joung et al. (1996) proposed that the mechanism of binding of p62 to the p56-lck SH2 domain is by a mechanism different from the previously characterized modes of binding of SH2 domains and their ligands.
Vadlamudi et al. (1996) used the yeast 2-hybrid system to identify proteins that interact with p62. They isolated 46 clones that tested positively for specific interaction with p62. Forty-three of the 46 clones were found by sequencing to be members of the ubiquitin family. Ubiquitination of cellular proteins is a crucial feature in regulation of signal transduction and cell cycle progression through ubiquitination-dependent proteasomal degradation of important cellular proteins. Vadlamudi et al. (1996) studied the interaction of p62 with ubiquitin by in vitro binding studies which showed that p62 binds noncovalently to ubiquitin. Vadlamudi et al. (1996) noted that p62 contains no homology with any known ubiquitin-binding protein and thus represents a new class of ubiquitin-binding protein.
Gong et al. (1999) found that the rat Zip1 and Zip2 isoforms differentially stimulated phosphorylation of Kv-beta-2 by PKC-zeta. Zip1 and Zip2 interacted to form heteromultimers, allowing for a hybrid stimulatory activity to PKC-zeta. Gong et al. (1999) found that Zip1 and Zip2 coexisted in the same cell type and were elevated differentially by neurotrophic factors. They suggested that these results provide a mechanism for specificity and regulation of PKC-zeta-targeted phosphorylation.
Clausen et al. (2010) reported that p62 recruited ALFY (WDFY3; 617485) to cytoplasmic p62 bodies upon amino acid starvation of HeLa cells. Both proteins were required for formation and autophagic degradation of cytoplasmic ubiquitin-positive inclusions and localized to nuclear PML (102578) bodies. The p62 homolog Ref2 accumulated in inclusions in brains of Drosophila carrying mutations in the ALFY homolog, blue cheese, indicating that ALFY is required for autophagic degradation of p62-associated ubiquitinated proteins. Clausen et al. (2010) concluded that p62 and ALFY interact to organize misfolded, ubiquitinated proteins into protein bodies that are degraded by autophagy.
By small interfering RNA-mediated knockdown of Rab factors in a murine macrophage line, Pilli et al. (2012) showed that inhibition of Rab8b (613532) caused a decrease in conversion of Mycobacterium bovis BCG phagosomes to degradative compartments after the induction of autophagy and autophagic killing of mycobacteria. Knockdown of Rab8b-interacting partners showed that Tbk1 (604834) was critical for autophagic killing of BCG by suppressing the maturation of autophagosomes. Coimmunoprecipitation, proximity ligation in situ analysis, and confocal microscopy revealed that Tbk1 associated with Rab8b on autophagic organelles. High-content imaging analysis showed that Tbk1 was required in bone marrow macrophages for phosphorylation of p62 on ser403, which was in turn required for autophagic function and clearance of p62 and associated cargo. Further analysis revealed that Il1b was necessary for the induction of autophagy in mycobacteria-infected macrophages and that Tbk1 was required for Il1b-induced autophagic elimination of M. tuberculosis.
Lee et al. (2012) showed that the atypical (i.e., nontuberculous) mycobacterium M. abscessus (Mabc) robustly activated the NLRP3 (606416) inflammasome in human macrophages via dectin-1 (CLEC7A; 606264)/SYK (600085)-dependent signaling and the cytoplasmic scaffold protein SQSTM1. Both dectin-1 and TLR2 (603028) were required for Mabc-induced expression of IL1B (147720), CAMP (600474), and DEFB4 (DEFB4A; 602215). Dectin-1-dependent SYK signaling, but not MYD88 (602170) signaling, led to activation of CASP1 (147678) and secretion of IL1B through a potassium efflux-dependent NLRP3/ASC (PYCARD; 606838) inflammasome. Mabc-induced SQSTM1 expression was also critically involved in NLRP3 inflammasome activation. Lee et al. (2012) concluded that the NLRP3/ASC inflammasome is critical for antimicrobial responses and innate immunity to Mabc infection.
The 2,870-nucleotide SQSTM1 transcript is contained within 8 exons distributed over a 16-kb genomic segment (Laurin et al., 2002).
Stumpf (2022) mapped the SQSTM1 gene to chromosome 5q35.3 based on an alignment of the SQSTM1 sequence (GenBank AK312451) with the genomic sequence (GRCh38).
Paget Disease of Bone 3
In a study of 24 French Canadian families and 112 unrelated individuals with Paget disease of bone, Laurin et al. (2002) confined the PDB3 locus (167250) on 5q35-qter to a region of approximately 300 kb. Within this interval, 2 disease-related haplotype signatures were observed in 11 families and 18 unrelated patients. This region encoded the SQSTM1 gene, which was a candidate gene for PDB because of its association with the RANK pathway (see 603499). Screening of SQSTM1 for mutations led to the identification of a recurrent nonconservative change (P392L; 601530.0001) flanking the ubiquitin-associated domain (UBA; position 394-440) of the protein that was not present in 291 control individuals. The data demonstrated that 2 independent mutational events at the same position in SQSTM1 cause Paget disease of bone in a high proportion of French Canadian patients.
Kurihara et al. (2007) found that osteoclast precursors from PDB patients with the P392L mutation and osteoclast precursors transduced with p62 protein carrying the P392L mutation were hyperresponsive to RANKL (TNFSF11; 602642) and TNF (191160) compared with control osteoclast precursors. Mice transgenic for P392L developed increased osteoclast numbers and progressive bone loss, but they did not manifest the increased osteoblast numbers seen in PDB. Kurihara et al. (2007) concluded that expression of P392L in osteoclasts is necessary to cause predisposition to PDB, but it is not sufficient for the full PDB phenotype.
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 3
Fecto et al. (2011) identified 9 different heterozygous missense mutations (see, e.g., P392L, 601530.0001 and A33V, 601530.0006) and 1 deletion in the SQSTM1 gene in 15 (2.8%) of 546 patients with amyotrophic lateral sclerosis (see FTDALS3, 616437). Six patients had a family history of the disorder, but DNA from relatives was not available for segregation analysis. All the mutations affected conserved residues, and none were present in the dbSNP or 1000 Genomes Project databases or in over 700 control individuals. Functional studies of the variants were not performed. The SQSTM1 gene was chosen as a candidate for direct sequencing because p62-positive aggregates have been found in neuronal and glial tissue from patients with various neurodegenerative disorders, including SOD1 (147450)-positive ALS1 (105400), Alzheimer disease (AD; 104300), Lewy body dementia (DLB; 127750), FUS (137070)-mutant ALS6 (608030), and FTDALS1 (105550). None of the patients had a personal or family history of PDB.
By direct sequencing of the SQSTM1 gene, Rubino et al. (2012) identified 3 missense variants in 3 of 170 Italian patients with FTD and 3 different missense variants in 3 of 124 Italian patients with ALS. None of the variants were found in 145 controls. Subsequent analysis identified 4 variants in the promoter region in 4 patients with FTD and 3 splice site variants in 1 patient with FTD and 3 with ALS. None of the variants were found in 145 control individuals or in 288 patients with Paget disease. Functional studies were not performed, and Rubino et al. (2012) suggested that further studies were warranted.
Hirano et al. (2013) identified 2 different heterozygous missense variants (A53T and P439L) in the SQSTM1 gene in 2 of 61 Japanese patients with ALS. Neither of the variants, which occurred at highly conserved residues, were detected in the dbSNP database or in 500 control Japanese chromosomes. Both patients had sporadic disease, yielding a frequency of 3.7% among 54 patients with sporadic ALS. Neither patient had evidence of Paget disease or dementia; functional studies of the variants were not performed.
Le Ber et al. (2013) identified 3 different heterozygous missense mutations in the SQSTM1 gene (see, e.g., 601530.0001 and 601530.0005) in 3 of 132 unrelated French families with FTD. The mutations were demonstrated to segregate with the disorder in 2 of the families. A heterozygous missense mutation (A33V; 601530.0006) was found in 1 of 56 probands with FTDALS. The mutation in the first family was found by exome sequencing; subsequent mutations were found by direct sequencing of the SQSTM1 gene in 187 French patients with FTD. In the family carrying the P392L mutation (601530.0001), all patients with FTD also had Paget disease. Functional studies of the variants were not performed. Overall, mutations were found in 4 (2%) of 188 patients with either FTD or FTDALS, indicating a low frequency of SQSTM1 mutations in FTD.
Neurodegeneration with Ataxia, Dystonia, and Gaze Palsy, Childhood-Onset
In 9 patients from 4 unrelated families with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Haack et al. (2016) identified 3 different homozygous loss-of-function mutations in the SQSTM1 gene (601530.0008-601530.0010). The mutations were found by exome sequencing and segregated with the disorder in the families; none of the heterozygous carriers had skeletal or neurologic abnormalities. Patient fibroblasts showed absence of the SQSTM1 protein as well as abnormalities in the early response to mitochondrial depolarization and autophagosome formation, as demonstrated by decreased perinuclear clustering of mitochondria after depolarization treatment. However, overall clearance of mitochondria was similar to controls after 24 hours, indicating redundant cellular mechanisms for mitochondrial removal.
In 10 patients from 3 consanguineous families with NADGP, Muto et al. (2018) identified homozygous mutations in the SQSTM1 gene (601530.0011-601530.0013). The mutations were identified by whole-exome sequencing and confirmed by Sanger sequencing. Studies in fibroblasts from the 2 affected sibs in family 1 demonstrated decelerated autophagic flux and impaired production of ubiquitin-positive protein aggregates in response to misfolded protein stress induced by MG132, a proteasomal inhibitor. Induction of mitochondrial depolarization in patient fibroblasts resulted in clustering of mitochondria around the nuclei and reduced ATP content.
Distal Myopathy with Rimmed Vacuoles
In 2 brothers and an unrelated man with adult-onset distal myopathy with rimmed vacuoles (DMRV; 617158), Bucelli et al. (2015) identified a heterozygous splice site mutation in the SQSTM1 gene (601530.0003). Analysis of patient cells and muscle tissue showed that the variant resulted in the expression of 2 different cryptically spliced abnormal isoforms that had distinct patterns of cellular expression. None of the patients had evidence of Paget disease or dementia.
Inactivation of constitutive autophagy results in formation of cytoplasmic protein inclusions and leads to liver injury and neurodegeneration. Using proteomic, immunoprecipitation, and immunofluorescence microscopy analyses, Komatsu et al. (2007) found that p62 interacted with LC3 (MAP1LC3A; 601242) in mouse lysosomes and autophagosomes. p62 accumulated in autophagy-deficient mouse livers and neurons lacking Atg5 (604261) or Atg7 (608760). Mice lacking p62 were fertile and lived more than 1 year, although they developed adult-onset obesity and diabetes. p62 -/- Atg7 -/- double-knockout mice did not accumulate ubiquitin protein inclusions in neurons or livers. Komatsu et al. (2007) concluded that p62 levels are regulated by autophagy and that the pathology of autophagy deficiency is cell type specific.
Muto et al. (2018) generated zebrafish sqstm1 knockdowns by use of morpholinos targeting the donor splice site of exon 2. Structural cerebellar defects were identified in about 60% of the embryos, ranging from depletion of axonal connections across the cerebellar midline to cerebellar atrophy. Coinjection of the zebrafish with human wildtype SQSTM1 rescued the phenotype.
Zach et al. (2018) developed and characterized a p62 -/- mouse model of PBD. In vitro studies demonstrated accelerated differentiation of osteoclasts, with elevated differentiation potential, multinucleation, and sRANKL activity in bone marrow-derived cells from the mutant mice. In vivo characterization of the mutant mice demonstrated an age-related PBD-like phenotype with both increased bone forming activity, including increased trabecular network in the femur and increased serum PINP, and increased bone degrading activity, including increased TRAP (171640) activity and serum CTX-I. Elevated proinflammatory cytokines, including TNF (191160), IL10 (124092), and IL1B (147720), were not detected in serum from the mutant mice. Michalski and Williams (2018) commented that these results help to clarify the role of p62 as a negative regulator of osteoclastogenesis.
Paget Disease of Bone 3
In 8 families showing linkage of Paget disease to the PDB3 locus on 5q (PDB3; 167250), Laurin et al. (2002) used a haplotype signature strategy to find ancestral haplotypes shared by affected individuals to narrow the mapping interval. The SQSTM1 gene, which maps to that interval, was found to have a C-to-T transition at position 1215 in exon 8 in all 5 affected individuals tested. This change caused the substitution of proline-392 to a leucine (P392L) in the ubiquitin-associated (UBA) domain of the protein. The P392L mutation was found in 18 (16%) of 112 sporadic cases and in 11 (46%) of 24 families with Paget disease tested. Haplotype analysis by means of intragenic SNPs showed that the P392L mutation was associated with 2 distinct haplotypes and probably originated from 2 independent events. This mutation, occurring at a hypermutable CpG dinucleotide, may have arisen by deamination of a methylated cytosine.
Using in vitro functional expression studies in E. coli, Cavey et al. (2005) showed that the P392L mutation caused loss of monoubiquitin binding and impaired K48-linked polyubiquitin binding when introduced into the full-length protein. The effect was observed only at physiologic temperature (37 degrees C) and not at room temperature or 4 degrees C. Cavey et al. (2005) speculated that the interaction of SQSTM1 with a ubiquitylated target may be central to the control of osteoclast NFKB1 (164011) signaling.
Rea et al. (2006) demonstrated that transfection of the P392L mutation into HEK293 cells resulted in increased NFKB1 activity compared to wildtype, suggesting a gain of function. The effects were cell type-specific, as similar results were not observed in COS-1 cells. Transfected cells showed increased osteoclast-like cell formation with dense nuclei compared to controls when stimulated with RANKL (TNFSF11; 602642).
Frontotemporal Dementia and/or Amyotrophic Lateral Sclerosis 3
In 3 of 546 patients with sporadic amyotrophic lateral sclerosis (FTDALS3; 616437), Fecto et al. (2011) identified a heterozygous P392L substitution, resulting from a c.1175C-T transition in exon 8 in the SQSTM1 gene. The mutation, which occurred at a conserved residue in the UBA domain, was not found in the dbSNP or 1000 Genomes Project databases or in 737 control individuals. Two of the patients had a family history of ALS, but DNA from family members was not available for segregation analysis. None of the patients had a personal or family history of PDB. Functional studies of the variant were not performed. Fecto et al. (2011) suggested that specific environmental factors or other modifier loci may be important in determining the specificity of the disease phenotype.
Le Ber et al. (2013) identified a heterozygous P392L mutation in 3 affected members of a French family (family FR1324) with FTDALS3, all of whom also had Paget disease of bone. Three older and unaffected individuals did not carry this mutation, indicating segregation within the family. PDB was diagnosed between ages 51 and 69; FTD was diagnosed between ages 59 and 79. None had symptoms of ALS. The P392L mutation was not found in 539 French controls.
Kwok et al. (2014) identified a heterozygous c.1175C-T transition (rs104893941) in the SQSTM1 gene, resulting in the P392L mutation, in 1 of 61 British probands with familial ALS. This patient also had Paget disease. Analysis of a second cohort of 26 patients with familial ALS identified 1 additional proband with the mutation, thus yielding an overall frequency of 2.3% for this mutation. Segregation studies of affected members in the families were not possible.
Van der Zee et al. (2014) identified a heterozygous P392L mutation in 15 of 1,808 patients with FTD and in 3 of 395 patients with ALS. The mutation was also found in 11 of 3,899 controls. Functional studies of the variant were not performed.
In affected members of 4 families with Paget disease of bone (PDB3; 167250), Hocking et al. (2002) identified a heterozygous 1-bp insertion (c.1224insT) in the SQSTM1 gene, predicted to result in premature termination at codon 396 in the ubiquitin-binding domain.
Paget Disease of Bone 3
In affected members of an Australian family with Paget disease of bone (PDB3; 167250), Hocking et al. (2002) identified heterozygosity for a G-to-A substitution at splice donor site IVS7+1 of the SQSTM1 gene. The mutation was predicted to result in skipping of exon 7, which encodes part of the ubiquitin-binding domain.
Distal Myopathy with Rimmed Vacuoles 2
In 2 brothers and an unrelated man with adult-onset distal myopathy with rimmed vacuoles (DMRV; 617158), Bucelli et al. (2015) identified a heterozygous c.1165+1G-A transition in intron 7 of the SQSTM1 gene. The mutation in the family was found by whole-exome sequencing; the mutation in the patient with sporadic disease was found by targeted exome sequencing. Analysis of patient cells and muscle tissue showed that the variant resulted in the expression of 2 different cryptically spliced abnormal isoforms, a deletion variant lacking the PEST2 domain and a truncating variant lacking the UBA domain. In vitro studies showed that the deletion and truncating SQSTM1 mutant proteins were translated and had distinct patterns of expression: 1 was excluded from the nucleus and did not colocalize with ubiquitin, whereas the other accumulated as large perinuclear inclusions that contained ubiquitin. Expression in murine myofibers showed that 1 of these variants was present throughout the sarcoplasm and associated with myofibrillar structures, whereas the other was found only as large subsarcolemmal and sarcoplasmic inclusions. None of the patients had evidence of Paget disease or dementia.
In a man with a severe form of Paget disease of bone (PDB3; 167250), Rea et al. (2006) identified a heterozygous c.1132A-T transversion in exon 7 of the SQSTM1 gene, resulting in a lys378-to-ter (K378X) substitution and elimination of the ubiquitin binding domain. In vitro functional expression studies in HEK293 cells showed that the mutation resulted in increased NFKB1 (164011) activity compared to wildtype. Transfected cells and patient cells also showed increased osteoclast-like cell formation with dense nuclei when stimulated with RANKL (602642), and patient-derived cells had enhanced bone resorptive activity compared to control.
In 3 French sibs (family F297) with frontotemporal dementia (FTDALS3; 616437), Le Ber et al. (2013) identified a heterozygous c.1160C-T transition (c.1160C-T, NM_003900.4) in the SQSTM1 gene, resulting in a pro387-to-leu (P387L) substitution at a highly conserved residue in the ubiquitin-binding domain. The mutation, which was found by exome-sequencing, segregated with the disorder in the family and was not present in the dbSNP (build 132), 1000 Genomes Project, or Exome Variant Server databases, in 50 in-house control exomes, or in 539 French controls. The patients had onset of the behavioral variant of dementia in their sixties and seventies; none had clinical symptoms of Paget disease of bone or amyotrophic lateral sclerosis. Functional studies of the variant were not performed.
Van der Zee et al. (2014) identified a heterozygous P387L mutation in 2 of 1,808 individuals with FTD. Both patients were of Italian descent; 1 had a family history of the disorder. The mutation was not found in 3,899 controls. Functional studies of the variant were not performed.
In a French proband with frontotemporal dementia and amyotrophic lateral sclerosis-3 (FTDALS3; 616437), Le Ber et al. (2013) identified a heterozygous c.98C-T transition (c.98C-T, NM_003900.4) in exon 1 of the SQSTM1 gene, resulting in an ala33-to-val (A33V) substitution There was a strong family history of the disorder, but segregation analysis could not be performed. The mutation was not found in 539 French controls. Functional studies of the variant were not performed.
The A33V mutation in the SH2-binding domain in SQSTM1 was originally identified by Fecto et al. (2011) in 3 unrelated patients with amyotrophic lateral sclerosis (FTDASL3; 616437). The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 724 controls. Two patients had sporadic disease and 1 had a family history of the disorder. Functional studies of the variant were not performed.
In 1 of 206 patients with sporadic amyotrophic lateral sclerosis (FTDALS3; 616437), Fecto et al. (2011) identified a heterozygous 3-bp in-frame deletion (c.714_716delGAA) in exon 5 of the SQSTM1 gene, resulting in the deletion of conserved residue lys238 (K238del) within the TRAF6 domain. The mutation was not found in the dbSNP or 1000 Genomes Project databases or in 724 controls. Functional studies of the variant were not performed.
Boutoleau-Bretonniere et al. (2015) identified a heterozygous c.714_716delGAA mutation in 3 French sibs with a variant of frontotemporal dementia. The mutation was not found in the Exome Variant Server database or in 350 French controls. The phenotype consisted of speech apraxia, visuoconstructional defects, executive dysfunction, and behavioral disorders, with onset between 70 and 75 years of age. None of the patients had evidence of Paget disease or ALS. Functional studies of the variant were not performed.
In 3 sibs, born of unrelated parents of German origin, with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Haack et al. (2016) identified a homozygous c.2T-A transversion (c.2T-A, NM003900.4) in exon 1 of the SQSTM1 gene. The mutation, which was found by a combination of exome sequencing and manual inspection of the sequencing data, was confirmed by Sanger sequencing. All 3 affected sibs were homozygous for the mutation, whereas the unaffected mother and healthy sibs were heterozygous; DNA from the father was not available. Heterozygous carriers showed no skeletal defects or neurologic disease. The findings were also consistent with linkage analysis on this family. Biallelic loss-of-function SQSTM1 mutations were not found in 7,000 in-house exomes or in the ExAC database. The c.2T-A mutation only affects the start codon of 1 out of 3 predicted isoforms. RNA sequencing in patient fibroblasts and blood suggested partial expression of the 2 other isoforms, but antibody against the C terminus of the protein common to all 3 isoforms failed to show any translated SQSTM1 protein, consistent with a loss-of-function effect.
In 3 sisters, born of apparently unrelated parents from the United Arab Emirates, with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Haack et al. (2016) identified a homozygous 2-bp deletion (c.311_312del, NM_003900.4) in exon 3 of the SQSTM1 gene, resulting in a frameshift and premature termination (Glu104ValfsTer48). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family, although DNA from the father was not available. Biallelic loss of function SQSTM1 mutations were not found in 7,000 in-house exomes or in the ExAC database. Patient fibroblasts showed absence of the SQSTM1 protein.
In 2 sibs, born of consanguineous Kurdish parents, with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Haack et al. (2016) identified a homozygous c.286C-T transition (c.286C-T, NM_003900.4) in exon 2 of the SQSTM1 gene, resulting in an arg96-to-ter (R96X) substitution. An unrelated girl of Finnish descent was also homozygous for this mutation; her parents were not related. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing in both families, was filtered against the ExAC database, and segregated with the disorder in the families. Biallelic loss of function SQSTM1 mutations were not found in 7,000 in-house exomes or in the ExAC database. Patient fibroblasts showed absence of the SQSTM1 protein.
In 2 sibs, born of consanguineous Italian parents (family 1), with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Muto et al. (2018) identified homozygosity for a T-A transition at the +2 position of intron 2 (c.301+2T-A, NM_003900.4) of the SQSTM1 gene. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Reverse transcriptase PCR in patient fibroblasts showed that the mutation resulted in skipping of exon 2, which was predicted to result in a protein lacking 34 amino acids of the N-terminal Phox and Bem1p domains, which are important for protein self-oligomerization. Analysis of patient fibroblasts showed lack of SQSTM1 protein expression.
In 2 sibs, born of consanguineous Iranian parents (family 2), with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Muto et al. (2018) identified homozygosity for a c.934_936delinsTGA mutation (c.934_936delinsTGA, NM_003900.4) in the SQSTM1 gene, predicted to result in an arg312-to-ter (R312X) substitution. The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family.
In 6 members of a consanguineous Iranian family (family 3) with childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy (NADGP; 617145), Muto et al. (2018) identified homozygosity for a 1-bp deletion (c.875insT, NM_003900.4) in the SQSTM1 gene, predicted to result in a frameshift and premature termination (Asp292fsTer9). The mutation, which was identified by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. The mutation was not present in public databases.
Boutoleau-Bretonniere, C., Camuzat, A., Le Ber, I., Bouya-Ahmed, K., Guerreiro, R., Deruet, A.-L., Evrard, C., Bras, J., Lamy, E., Auffray-Calvier, E., Pallardy, A., Hardy, J., Brice, A., Derkinderen, P., Vercelletto, M. A phenotype of atypical apraxia of speech in a family carrying SQSTM1 mutation. J. Alzheimers Dis. 43: 625-630, 2015. [PubMed: 25114083] [Full Text: https://doi.org/10.3233/JAD-141512]
Bucelli, R. C., Arhzaouy, K., Pestronk, A., Pittman, S. K., Rojas, L., Sue, C. M., Evila, A., Hackman, P., Udd, B., Harms, M. B., Weihl, C. C. SQSTM1 splice site mutation in distal myopathy with rimmed vacuoles. Neurology 85: 665-674, 2015. [PubMed: 26208961] [Full Text: https://doi.org/10.1212/WNL.0000000000001864]
Cavey, J. R., Ralston, S. H., Hocking, L. J., Sheppard, P. W., Ciani, B., Searle, M. S., Layfield, R. Loss of ubiquitin-binding associated with Paget's disease of bone p62 (SQSTM1) mutations. J. Bone Miner. Res. 20: 619-624, 2005. [PubMed: 15765181] [Full Text: https://doi.org/10.1359/JBMR.041205]
Clausen, T. H., Lamark, T., Isakson, P., Finley, K., Larsen, K. B., Brech, A., Overvatn, A., Stenmark, H., Bjorkoy, G., Simonsen, A., Johansen, T. p62/SQSTM1 and ALFY interact to facilitate the formation of p62 bodies/ALIS and their degradation by autophagy. Autophagy 6: 330-344, 2010. [PubMed: 20168092] [Full Text: https://doi.org/10.4161/auto.6.3.11226]
Fecto, F., Yan, J., Vemula, S. P., Liu, E., Yang, Y., Chen, W., Zheng, J. G., Shi, Y., Siddique, N., Arrat, H., Donkervoort, S., Ajroud-Driss, S., Sufit, R. L., Heller, S. L., Deng, H.-X., Siddique, T. SQSTM1 mutations in familial and sporadic amyotrophic lateral sclerosis. Arch. Neurol. 68: 1440-1446, 2011. [PubMed: 22084127] [Full Text: https://doi.org/10.1001/archneurol.2011.250]
Gong, J., Xu, J., Bezanilla, M., van Huizen, R., Derin, R., Li, M. Differential stimulation of PKC phosphorylation of potassium channels by ZIP1 and ZIP2. Science 285: 1565-1569, 1999. [PubMed: 10477520] [Full Text: https://doi.org/10.1126/science.285.5433.1565]
Haack, T. B., Ignatius, E., Calvo-Garrido, J., Iuso, A., Isohanni, P., Maffezzini, C., Lonnqvist, T., Suomalainen, A., Gorza, M., Kremer, L. S., Graf, E., Hartig, M. and 21 others. Absence of the autophagy adaptor SQSTM1/p62 causes childhood-onset neurodegeneration with ataxia, dystonia, and gaze palsy. Am. J. Hum. Genet. 99: 735-743, 2016. [PubMed: 27545679] [Full Text: https://doi.org/10.1016/j.ajhg.2016.06.026]
Hirano, M., Nakamura, Y., Saigoh, K., Sakamoto, H., Ueno, S., Isono, C., Miyamoto, K., Akamatsu, M., Mitsui, Y., Kusunoki, S. Mutations in the gene encoding p62 in Japanese patients with amyotrophic lateral sclerosis. Neurology 80: 458-463, 2013. [PubMed: 23303844] [Full Text: https://doi.org/10.1212/WNL.0b013e31827f0fe5]
Hocking, L. J., Lucas, G. J. A., Daroszewska, A., Mangion, J., Olavesen, M., Cundy, T., Nicholson, G. C., Ward, L., Bennett, S. T., Wuyts, W., Van Hul, W., Ralston, S. H. Domain-specific mutations in sequestosome 1 (SQSTM1) cause familial and sporadic Paget's disease. Hum. Molec. Genet. 11: 2735-2739, 2002. [PubMed: 12374763] [Full Text: https://doi.org/10.1093/hmg/11.22.2735]
Joung, I., Strominger, J. L., Shin, J. Molecular cloning of a phosphotyrosine-independent ligand of the p56-lck SH2 domain. Proc. Nat. Acad. Sci. 93: 5991-5995, 1996. [PubMed: 8650207] [Full Text: https://doi.org/10.1073/pnas.93.12.5991]
Komatsu, M., Waguri, S., Koike, M., Sou, Y., Ueno, T., Hara, T., Mizushima, N., Iwata, J., Ezaki, J., Murata, S., Hamazaki, J., Nishito, Y. {and 13 others}: Homeostatic levels of p62 control cytoplasmic inclusion body formation in autophagy-deficient mice. Cell 131: 1149-1163, 2007. [PubMed: 18083104] [Full Text: https://doi.org/10.1016/j.cell.2007.10.035]
Kurihara, N., Hiruma, Y., Zhou, H., Subler, M. A., Dempster, D. W., Singer, F. R., Reddy, S. V., Gruber, H. E., Windle, J. J., Roodman, G. D. Mutation of the sequestosome 1 (p62) gene increases osteoclastogenesis but does not induce Paget disease. J. Clin. Invest. 117: 133-142, 2007. [PubMed: 17187080] [Full Text: https://doi.org/10.1172/JCI28267]
Kwok, C. T., Morris, A., de Belleroche, J. S. Sequestosome-1 (SQSTM1) sequence variants in ALS cases in the UK: prevalence and coexistence of SQSTM1 mutations in ALS kindred with PDB. Europ. J. Hum. Genet. 22: 492-496, 2014. [PubMed: 23942205] [Full Text: https://doi.org/10.1038/ejhg.2013.184]
Laurin, N., Brown, J. P., Morissette, J., Raymond, V. Recurrent mutation of the gene encoding sequestosome 1 (SQSTM1/p62) in Paget disease of bone. Am. J. Hum. Genet. 70: 1582-1588, 2002. [PubMed: 11992264] [Full Text: https://doi.org/10.1086/340731]
Le Ber, I., Camuzat, A., Guerreiro, R., Bouya-Ahmed, K., Bras, J., Nicolas, G., Gabelle, A., Didic, M., De Septenville, A., Millecamps, S., Lenglet, T., Latouche, M., Kabashi, E., Campion, D., Hannequin, D., Hardy, J., Brice, A. SQSTM1 mutations in French patients with frontotemporal dementia or frontotemporal dementia with amyotrophic lateral sclerosis. JAMA Neurol. 70: 1403-1410, 2013. [PubMed: 24042580] [Full Text: https://doi.org/10.1001/jamaneurol.2013.3849]
Lee, H.-M., Yuk, J.-M., Kim, K.-H., Jang, J., Kang, G., Park, J. B., Son, J.-W., Jo, E.-K. Mycobacterium abscessus activates the NLRP3 inflammasome via dectin-1-Syk and p62/SQSTM1. Immun. Cell Biol. 90: 601-610, 2012. [PubMed: 21876553] [Full Text: https://doi.org/10.1038/icb.2011.72]
Michalski, M. N., Williams, B. O. A quest for clarity in bone erosion: the role of sequestosome 1 in Paget's disease of bone. J. Biol. Chem. 293: 9542-9543, 2018. [PubMed: 29907733] [Full Text: https://doi.org/10.1074/jbc.H118.003689]
Muto, V., Flex, F., Kupchinsky, Z., Primiano, G., Galehdari, H., Dehghani, M., Cecchetti, S., Carpentieri, G., Rizza, T., Mazaheri, N., Sedaghat, A., Vahidi Mehrjardi, M. Y., and 19 others. Biallelic SQSTM1 mutations in early-onset, variably progressive neurodegeneration. Neurology 91: e319-e330, 2018. [PubMed: 29959261] [Full Text: https://doi.org/10.1212/WNL.0000000000005869]
Park, I., Chung, J., Walsh, C. T., Yun, Y., Strominger, J. L., Shin, J. Phosphotyrosine-independent binding of a 62-kDa protein to the src homology 2 (SH2) domain of p56-lck and its regulation by phosphorylation of ser-59 in the lck unique N-terminal region. Proc. Nat. Acad. Sci. 92: 12338-12342, 1995. [PubMed: 8618896] [Full Text: https://doi.org/10.1073/pnas.92.26.12338]
Pilli, M., Arko-Mensah, J., Ponpuak, M., Roberts, E., Master, S., Mandell, M. A., Dupont, N., Ornatowski, W., Jiang, S., Bradfute, S. B., Bruun, J.-A., Hansen, T. E., Johansen, T., Deretic, V. TBK-1 promotes autophagy-mediated antimicrobial defense by controlling autophagosome maturation. Immunity 37: 223-234, 2012. [PubMed: 22921120] [Full Text: https://doi.org/10.1016/j.immuni.2012.04.015]
Rea, S. L., Majcher, V., Searle, M. S., Layfield, R. SQSTM1 mutations--bridging Paget disease of bone and ALS/FTD. Exp. Cell Res. 325: 27-37, 2014. [PubMed: 24486447] [Full Text: https://doi.org/10.1016/j.yexcr.2014.01.020]
Rea, S. L., Walsh, J. P., Ward, L., Yip, K., Ward, B. K., Kent, G. N., Steer, J. H., Xu, J., Ratajczak, T. A novel mutation (K378X) in the sequestosome 1 gene associated with increased NF-kappa-beta signaling and Paget's disease of bone with a severe phenotype. J. Bone Miner. Res. 21: 1136-1145, 2006. [PubMed: 16813535] [Full Text: https://doi.org/10.1359/jbmr.060405]
Rubino, E., Rainero, I., Chio, A., Rogaeva, E., Galimberti, D., Fenoglio, P., Grinberg, Y., Isaia, G., Calvo, A., Gentile, S., Bruni, A. C., St. George-Hyslop, P. H., Scarpini, E., Gallone, S., Pinessi, L. SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis. Neurology 79: 1556-1562, 2012. [PubMed: 22972638] [Full Text: https://doi.org/10.1212/WNL.0b013e31826e25df]
Stumpf, A. M. Personal Communication. Baltimore, Md. 01/24/2022.
Vadlamudi, R. K., Joung, I., Strominger, J. L., Shin, J. p62, a phosphotyrosine-independent ligand of the SH2 domain of p56-lck, belongs to a new class of ubiquitin-binding proteins. J. Biol. Chem. 271: 20235-20237, 1996. [PubMed: 8702753] [Full Text: https://doi.org/10.1074/jbc.271.34.20235]
van der Zee, J., Van Langenhove, T., Kovacs, G. G., Dillen, L., Deschamps, W., Engelborghs, S., Matej, R., Vandenbulcke, M., Sieben, A., Dermaut, B., Smets, K., Van Damme, P., and 68 others. Rare mutations in SQSTM1 modify susceptibility to frontotemporal lobar degeneration. Acta Neuropath. 128: 397-410, 2014. [PubMed: 24899140] [Full Text: https://doi.org/10.1007/s00401-014-1298-7]
Zach, F., Polzer, F., Mueller, A., Gessner, A. p62/sequestosome 1 deficiency accelerates osteoclastogenesis in vitro and leads to Paget's disease-like bone phenotypes in mice. J. Biol. Chem. 293: 9530-9541, 2018. [PubMed: 29555685] [Full Text: https://doi.org/10.1074/jbc.RA118.002449]