SQSTM1 Gene: Clinical Implications and Management
SQSTM1 (sequestosome 1/p62) gene mutations cause distinct clinical phenotypes depending on inheritance pattern: biallelic loss-of-function mutations cause childhood-onset neurodegeneration with ataxia and dystonia, while heterozygous mutations primarily cause Paget's disease of bone (PDB) and may contribute to amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). 1, 2, 3
Clinical Phenotypes by Mutation Type
Biallelic Loss-of-Function Mutations (Recessive)
Childhood/adolescence-onset neurodegenerative disorder characterized by:
- Gait abnormalities and ataxia 1
- Dysarthria and dystonia 1
- Vertical gaze palsy 1
- Progressive cognitive decline 1
- Complete absence of SQSTM1/p62 protein in patient fibroblasts 1
- Defective mitochondrial depolarization response and impaired autophagosome formation 1
Heterozygous Mutations (Dominant/Risk Factor)
Paget's Disease of Bone (PDB):
- Mutations detected in approximately 10-11% of PDB patients 4
- All identified mutations affect the ubiquitin-associated (UBA) domain 2
- Earlier age at diagnosis (59.4 vs 65.0 years in non-carriers) 4
- Greater number of affected bones (3.2 vs 2.1 bones) 4
- Increased requirement for orthopedic surgery (26.2% vs 16.1%) 4
- Higher need for bisphosphonate therapy (86.3% vs 75.2%) 4
- Reduced quality of life (SF36 physical summary score: 34.0 vs 37.1) 4
- Increased fracture risk (12.5% vs 5.3%), though most occur in unaffected bone 4
ALS/Frontotemporal Lobar Degeneration:
- SQSTM1 mutations identified in small subset of ALS/FTLD patients 3
- Some mutations are ALS/FTLD-specific, while others overlap with PDB-associated mutations 3
Molecular Mechanisms
SQSTM1/p62 functions as:
- Selective autophagy receptor linking ubiquitinated proteins to LC3 via WXXL/LIR motif 5
- Regulator of KEAP1 degradation, controlling NFE2L2/NRF2 antioxidant responses 5
- Mediator of SLC40A1/ferroportin degradation affecting iron homeostasis 5
- Protein that accumulates when macroautophagy is inhibited 5
- Interactor with HDAC6 to regulate microtubule acetylation and autophagosome turnover 5
Mouse models demonstrate causality:
- P394L mutation (equivalent to human P392L) causes PDB-like disorder without environmental trigger 6
- 77% of heterozygotes and 95% of homozygotes develop focal bone lesions by 12 months 6
- Osteoclast precursors show increased RANKL sensitivity and dysregulated autophagy 6
- Increased expression of autophagy markers (atg5, lc3) and enhanced autophagosome formation 6
Diagnostic Approach
For suspected PDB with family history or severe disease:
- Genetic testing for SQSTM1 mutations targeting the UBA domain 2, 4
- Identify patients at risk for severe disease complications 4
For childhood-onset neurodegeneration with ataxia/dystonia:
- Exome sequencing to identify biallelic SQSTM1 loss-of-function variants 1
- Confirm absence of SQSTM1/p62 protein in patient fibroblasts 1
- Assess mitochondrial depolarization response and autophagosome formation 1
For ALS/FTLD patients:
- Consider SQSTM1 mutation screening, particularly if family history of PDB 3
Management Strategies
For PDB with SQSTM1 mutations:
- Early bisphosphonate therapy given higher treatment requirements (86.3% of carriers) 4
- Increased orthopedic surveillance due to 26.2% surgery rate 4
- Monitor for fracture risk (12.5% incidence) 4
- Consider prophylactic intervention in genetically confirmed cases before symptom onset 4
For biallelic SQSTM1-related neurodegeneration:
- Supportive management targeting specific symptoms (ataxia, dystonia, gaze palsy) 1
- Monitor for progressive cognitive decline 1
- No specific disease-modifying therapy currently available 1
Critical Caveats
Genetic testing interpretation:
- Most fractures in PDB mutation carriers occur in unaffected bone, suggesting systemic effects 4
- Cost-effectiveness of genetic screening programs requires further validation 4
- Phenotypic variability exists even among mutation carriers 4
Autophagy monitoring considerations: