Ubiquitin-associated domain mutations of SQSTM1 in Paget's disease of bone: evidence for a founder effect in patients of British descent.
Mutations in the UBA domain of SQSTM1 are a common cause of Paget's disease of bone. Here we show that the most common disease-causing mutation (P392L) is carried on a shared haplotype, consistent with a founder effect and a common ancestral origin.


BACKGROUND
Paget's disease of bone (PDB) is a common condition with a strong genetic component. Mutations affecting the ubiquitin-associated (UBA) domain of sequestosome 1 (SQSTM1) have recently been shown to be an important cause of PDB. The most common mutation results in a proline to leucine amino acid change at codon 392 (P392L), and evidence has been presented to suggest that there may be a recurrent mutation rather than a founder mutation on an ancestral chromosome. Because marked geographical differences exist in the prevalence of PDB, we have investigated the frequency of SQSTM1 mutations in different populations and looked for a founder effect on chromosomes bearing SQSTM1 UBA domain mutations.


METHODS
We conducted mutation screening of SQSTM1 and performed haplotype analysis using the PHASE software program in 83 kindreds with familial PDB, recruited mainly through clinic referrals in the United Kingdom, Australia, and New Zealand. Similar studies were conducted in 311 individuals with PDB who did not have a family history and 375 age- and sex-matched controls from the United Kingdom.


RESULTS
The proportion of patients with familial PDB who had SQSTM1 UBA domain mutations varied somewhat between referral centers from 7.1% (Sydney, Australia) to 50% (Perth, Australia), but the difference between centers was not statistically significant. Haplotype analysis in 311 British patients with PDB who did not have a family history and 375 age- and sex-matched British controls showed that two common haplotypes accounted for about 90% of alleles at the SQSTM1 locus, as defined by common single nucleotide polymorphisms (SNPs) in exon 6 (C916T, G976A) and the 3'UTR (C2503T, T2687G). These were H1 (916T-976A-2503C-2687T) and H2 (916C-976G-2503T-2687G). There was no significant difference in haplotype distribution in PDB cases and controls, but the P392L mutation was found on the H2 haplotype in 25/27 cases (93%), which is significantly more often than expected given the allele frequencies in the normal population (odds ratio, 13.2; 95% CI, 3.1-56.4; p < 0.0001). Similar findings were observed in familial PDB, where 12/13 (92%) of P392L mutations were carried on H2 (odds ratio 17.2; 95% CI, 2.2-138; p = 0.001).


CONCLUSIONS
These results provide strong evidence for a founder effect of the SQSTM1 P392L mutation in PDB patients of British descent, irrespective of family history. Our results imply that these individuals share a common ancestor and that the true rate of de novo mutations may be lower than previously suspected.
Lucas
Gavin J A
GJ
Department of Medicine and Therapeutics, University of Aberdeen, Aberdeen, United Kingdom.
Hocking
Lynne J
LJ
Daroszewska
Anna
A
Cundy
Tim
T
Nicholson
Geoff C
GC
Walsh
John P
JP
Fraser
William D
WD
Meier
Christian
C
Hooper
Michael J
MJ
Ralston
Stuart H
SH
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D017931:DNA Primers / Q000737:chemistry; D005091:Exons; D005260:Female; D018703:Founder Effect; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007438:Introns; D008297:Male; D008957:Models, Genetic; D009154:Mutation; D016017:Odds Ratio; D010001:Osteitis Deformans / Q000208:ethnology* / Q000235:genetics* / Q000378:metabolism*; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000235:genetics*; D000071456:Sequestosome-1 Protein; D012984:Software; D025801:Ubiquitin / Q000737:chemistry*; D006113:United Kingdom
D020413:3' Untranslated Regions; D048868:Adaptor Proteins, Signal Transducing; D017931:DNA Primers; D011506:Proteins; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; D025801:Ubiquitin