Sequestosome 1: Mutation Frequencies, Haplotypes, and Phenotypes in Familial Paget's Disease of Bone

Abstract

Mutations of the SQSTM1/p62 gene are commonly observed in PDB. Screening an updated sample from Quebec and using previously published data from other populations, we compared frequency estimates for SQSTM1/p62 mutations and haplotype distribution. The P392L mutation was the most prevalent, embedded in two different haplotypes, possibly shared by other populations. We also examined the phenotype and penetrance of P392L. Introduction:There is accumulating evidence that supports a contribution of genetic factors in the etiology of Paget's disease of bone (PDB), and several genetic loci have been suggested for the disorder. The sequestosome1/p62 (SQSTM1/p62) gene was the first gene identified to have a role in PDB, with 14 mutations reported to date. Material and Methods:To evaluate the importance of the SQSTM1/p62 mutations in PDB, we recruited, sequenced, and genotyped a total of 123 carriers from 20 families in addition to 214 unrelated PDB patients. We compared the frequency of SQSTM1/p62 mutations in familial and unrelated cases among different populations. Finally, we examined the phenotypic expression and penetrance of the P392L mutation in the Quebecois families. Results and Conclusions:The 14 mutations reported in SQSTM1/p62 all affect the ubiquitin-associated domain of the protein. The P392L mutation is the most commonly observed mutation in PDB patients and was consistently found in unrelated and familial PDB cases in the populations tested. Analysis of adjacent polymorphisms suggests that P392L is associated with two different haplotypes in the Quebecois patients, similar to what has been observed in European populations. In Quebec, both haplotypes had similar frequencies in unrelated P392L carriers, whereas one haplotype was predominant in the other populations studied. These data suggest that these two haplotypes, possibly introduced by European founders in the Quebecois population, were equally distributed in the succeeding generations. Finally, the P392L mutation is transmitted as an autosomal dominant trait in the Quebecois families, with a high but incomplete penetrance peaking after age 60. The large phenotypic variability and similarity between unrelated and familial cases, respectively, remain unexplained and require further research. J Bone Miner Res 2007;21:P38-P44. Online reference number: doi: 00.0000/JBMR.065S207

SQSTM1 gene analysis and gene-environment interaction in Paget's disease of bone

“…(21) Even though a slight reduction in clinical severity and a higher variation in the number of affected skeletal sites among family members were observed in missense with respect to truncating mutations, we can conclude that there are no major genotype-phenotype differences in relation to the type or site of SQSTM1 mutation. Together with the described cases of incomplete penetrance (20)(21)(22) and the examples of phenocopy observed in this and other previous studies, (19) these findings further reinforce the hypothesis that additional factors may be required to cause the disease (at least in a group of patients) as well as its skeletal extension in subjects with or without SQSTM1 mutations. In this context, the presence of somatically acquired SQSTM1 mutations in the pagetic bone cannot be excluded, even though this hypothesis remains controversial and probably restricted to a limited number of patients.…”

“…Consistent with previous studies in different populations, (8,22,30,31) the H 1 (916T-976A-2503C-2687T) and H 2 (916C-976G-2503T-2687G) haplotypes accounted for the largest proportion of patients (94.3%) and controls (91.5%). The remaining patients were accounted for by six rare haplotypes with individual frequencies of between 0.2% and 3.6%.…”

“…Moreover, we also observed two H 1 -H 1 homozygous patients carrying the P392L mutation, suggesting that the same mutation has occurred independently at least twice, as observed previously in the French-Canadian population. (8,22) An increased prevalence of the H 2 haplotype also was seen in patients with the M404V mutation, whereas the Y383X mutation was carried with the H 2 haplotype in all patients. This also strongly supports the presence of a founder effect for this mutation.…”

“…All the remaining exons and intron-exon boundaries of SQSTM1 also were screened in familial PDB patients who did not show mutations in exons 7 and 8. To analyze the genetic background of mutated patients, we genotyped four single-nucleotide polymorphisms (SNPs) located in exon 6 (C916T, G976A) and the 3' untranslated region of SQSTM1 (C2503T, T2687G) as performed in previous studies. (8,22,30,31) The software program PHASE was used to reconstruct haplotypes (www.stat.washington.edu/stephens/).…”

“…(11,16,17,(19)(20)(21) Despite the fact that SQSTM1 mutations have been associated with a consistent number of familial PDB cases, incomplete penetrance has been described, and the prevalence of these mutations is low in sporadic PDB. (20)(21)(22) Moreover, even in PDB families with SQSTM1 mutations, some affected relatives without the mutation were described, suggesting that additional factors (either genetic or exogenous) may be associated with disease expression. (19) This is in keeping with results from experimental animal models of PDB.…”