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Published on: August 20, 2019
Clinical and cellular phenotypes associated with sequestosome 1 (SQSTM1) mutations
Robin J Leach1, Frederick R Singer, Yasmin Ench
1Department of Cellular and Structural Biology, University of Texas Health Science Center, San Antonio, Texas 78284, USA. leach@uthscsa.edu
Summary
Mutations in the SQSTM1 gene
Area of Science:
- Genetics
- Molecular Biology
- Bone Diseases
Background:
- Familial Paget's disease of bone is linked to mutations in the sequestosome 1 (SQSTM1) gene's ubiquitin-associated (UBA) domain.
- SQSTM1 mutations are a known genetic factor in Paget's disease.
Purpose of the Study:
- To investigate the clinical and molecular characteristics of familial Paget's disease associated with SQSTM1 UBA domain mutations.
- To explore the variable expressivity and incomplete penetrance of SQSTM1 mutations in Paget's disease.
Main Methods:
- Clinical assessment of five families with diverse backgrounds harboring SQSTM1 UBA domain mutations.
- Molecular studies of SQSTM1 protein aggregation phenotypes.
- Analysis of genotype-phenotype correlations.
Main Results:
- SQSTM1 UBA domain mutations (P387L, P392L, D391fsX394, P392fsX394) were identified in all families.
- Highly variable intrafamilial expressivity and incomplete penetrance were observed, with 18 carriers showing no disease.
- Point mutations led to larger cytoplasmic aggregates than wildtype or truncation mutations, but this did not correlate with clinical presentation.
Conclusions:
- SQSTM1 mutations confer predisposition to familial Paget's disease but exhibit variable expressivity and incomplete penetrance.
- Cellular aggregation phenotypes differ based on mutation type, yet clinical outcomes are not directly predictable from genotype.
- Nongenetic factors likely play a significant role in Paget's disease pathogenesis.
