ABCMdb

PMID: 12384774

Le Saux O, Beck K, Sachsinger C, Treiber C, Goring HH, Curry K, Johnson EW, Bercovitch L, Marais AS, Terry SF, Viljoen DL, Boyd CD
Evidence for a founder effect for pseudoxanthoma elasticum in the Afrikaner population of South Africa.
Hum Genet. 2002 Oct;111(4-5):331-8. Epub 2002 Sep 7., [PubMed]

Sentences

No. Mutations Sentence Comment

51 ABCC6 p.Arg1339Cys One missense allele, R1339C, represented more than half (53%) the total number of Afrikaner mutant alleles (Table 2). Login to comment 52 ABCC6 p.Arg1138Gln ABCC6 p.Leu673Pro Other ABCC6 mutant alleles included two missense mutations, R1138Q and L673P, which occurred at frequencies of 8.8% (3 out of 34 alleles) and 2.9% (1 out of 34 alleles), respectively. Login to comment 53 ABCC6 p.Arg1141* ABCC6 p.Tyr768* Two nonsense variants (Y768X and R1141X) and a single frameshift mutation (939insT) were also identified (Table 1). Login to comment 55 ABCC6 p.Arg1141* Two of the mutations found in the Afrikaner group, R1141X and 939insT, were also found in PXE individuals of British ancestries (Tables 1, 2). Login to comment 56 ABCC6 p.Arg1141* One of the latter individuals (from Family 212) carried the R1141X allele in association with 939insT. Login to comment 58 ABCC6 p.Arg1141* Moreover, two of the four R1141X alleles found in Afrikaner and British individuals occurred in similar haplotypes, also suggesting a possible consanguineous relationship between Family 206 (Afrikaner) and Family 216 (British ancestry). Login to comment 59 ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Gln ABCC6 p.Arg1138Gln ABCC6 p.Arg518Gln ABCC6 p.Arg1030* ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Arg1339Cys ABCC6 p.Leu673Pro ABCC6 p.Tyr768* ABCC6 p.Tyr768* ABCC6 p.Tyr768* ABCC6 p.Tyr768* The remaining R1141X mutations, characterized in Family 224 (Afrikaner) and Family 212 (British ancestry) were found in different haplotypes indicating that 333 Table 1 ABCC6 mutations identified in a cohort of South African PXE patients of Afrikaner and other ancestries (nt nucleotide, aa amino acid, ni not identified, UK United Kingdom, Black black South Africans) Family Allele 1 Allele 2 Ancestry nt change aa change Exon Haplotype nt change aa change Exon Haplotype 201 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 203 4015C→T R1339C 28 I 3413G→A R1138Q 24 III Afrikaner 205 3413G→A R1138Q 24 III 2304C→A Y768X 18 II Afrikaner 206 4015C→T R1339C 28 I 3421C→T R1141X 24 Other Afrikaner 208 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 209 4015C→T R1339C 28 I 2018T→C L673P 16 Other Afrikaner 211 4015C→T R1339C 28 I 3413G→A R1138Q 24 III Afrikaner 222 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 223 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 225 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 226 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 228 4015C→T R1339C 28 I 2304C→A Y768X 18 II Afrikaner 229 4015C→T R1339C 28 I 4015C→T R1339C 28 I Afrikaner 213 939insT Frameshift 8 Other ni ni ni Other Afrikaner 214 4015C→T R1339C 28 I ni ni ni Other Afrikaner 224 3421C→T R1141X 24 Other ni ni ni Other Afrikaner 204 ni ni Other ni ni ni Other Afrikaner 212 3421C→T R1141X 24 Other 939insT Frameshift 8 Other UK 215 3775delT Frameshift 27 Other 4104delC Frameshift 29 Other UK 217 ABCC6del15 Frameshift 15 Other ABCC6del15 Frameshift 15 Other Indian 207 3088C→T R1030X 23 Other ni ni ni Other UK 216 3421C→T R1141X 24 Other ni ni ni Other UK 219 1553G→A R518Q 12 Other ni ni ni Other UK 221 ni ni Other ni ni ni Other Black Table 2 Frequencies of mutant ABCC6 alleles found in a cohort of PXE patients of Afrikaner and other ancestries (? Login to comment 60 ABCC6 p.Arg1141* ABCC6 p.Arg1138Gln ABCC6 p.Arg518Gln ABCC6 p.Arg1030* ABCC6 p.Arg1339Cys ABCC6 p.Leu673Pro ABCC6 p.Tyr768* unidentified alleles, MDR mutation detection rate) Mutation Overall Afrikaner ancestries Others ancestries Allele Allele Allele Allele Allele Allele count frequency (%) count frequency (%) count frequency (%) R1339C 18 37.5 18 52.9 0 0 Y768X 4 8.3 4 11.8 0 0 R1141X 4 8.3 2 5.9 2 14.3 R1138Q 3 6.3 3 8.8 0 0 939insT 2 4.2 1 2.9 1 7.1 ABCC6del15 2 4.2 0 0.0 2 14.3 L673P 1 2.1 1 2.9 0 0.0 R1030X 1 2.1 0 0.0 1 7.1 R518Q 1 2.1 0 0.0 1 7.1 3775delT 1 2.1 0 0.0 1 7.1 4104delC 1 2.1 0 0.0 1 7.1 ? Login to comment 66 ABCC6 p.Arg1138Gln ABCC6 p.Arg1339Cys ABCC6 p.Tyr768* Three major haplotypes, with some variation at single markers, encompassing the PXE locus (located between markers D16S405 and D16S764; Le Saux et al. 1999; Cai et al. 2000) were identified (Fig.1) and three disease alleles (R1339C, Y768X, R1138Q) were found to be strictly associated with these three haplotypes (referred to as types I, II and III; Fig.1). Login to comment 81 ABCC6 p.Arg1339Cys ABCC6 p.Tyr768* ABCC6 p.Arg1138* The three disease alleles, R1339C, Y768X, and R1138X, associated with the type I, II and III haplotypes represent three ancestral founder alleles from which 74% of the Afrikaner alleles have descended. Login to comment 83 ABCC6 p.Arg1141* ABCC6 p.Leu673Pro All other mutated alleles, R1141X, L673P, 939insT and particularly the five unidentified mutations, were found in divergent haplotypes. Login to comment 84 ABCC6 p.Arg1141* ABCC6 p.Leu673Pro The latter three alleles (R1141X, L673P and 939insT) could have been introduced by founder individuals or could represent de novo mutation events in the Afrikaner population. Login to comment 89 ABCC6 p.Arg1268Gln ABCC6 p.Val614Ala ABCC6 p.Gly61Asp ABCC6 p.Ile1350Leu 335 Table 3 Silent and neutral variants identified in the ABCC6 gene in a cohort of 24 South African patients with PXE (hm homozygote, ht heterozygote, aa amino acid changes, nt nucleotide changes, i- the intron in which the variant is located, No. of alleles number of variants found in the 48 PXE chromosomes analysed in this study aVariants identified by sequencing only; variants identified in either or both ABCC6 pseudogenes have not been indicated in this table aa nt Status Exon Origin No. of alleles G61D 182G→A ht 2 Afrikaner 1 T215T 645G→A ht 6 Afrikaner 2 K281Ea 841A→G ht, hm 8 Afrikaner, UK 2 T285Ta 855C→T ht, hm 8 Afrikaner, UK 2 I319Va 955A→G ht, hm 8 Afrikaner, UK 2 N411N 1233T→C ht, hm 10 Afrikaner, UK 20 V415V 1245G→A ht, hm 10 All 20 none IVS11+73G→C ht i-11 Afrikaner, UK 2 none IVS11-45C→A ht i-11 UK 1 none IVS11-41A→G ht, hm i-11 Afrikaner, UK 5 none IVS11-22C→A ht i-11 Afrikaner 1 V614A 1841T→C ht, hm 14 All 16 T630Ta 1890C→G ht, hm 15 Afrikaner, UK 11 H632Qa 1896C→A ht, hm 15 Afrikaner, UK 11 A830A 2490C→T ht, hm 19 Afrikaner, UK 6 none IVS21+30G→A ht i-21 UK 2 P945P 2835C→T ht, hm 22 Indian, UK 3 none IVS22-5delTCCC-8 ht i-22 UK 1 none IVS24-16T→C ht i-24 UK 1 none IVS24-3C→T ht i-24 AFK 1 none IVS25+55T→C ht i-25 Afrikaner, UK 8 none IVS25+90G→A ht, hm i-25 All 21 R1268Q 3803G→A ht, hm 27 Afrikaner, UK 4 none IVS27-6G→A ht i-27 Afrikaner 1 none IVS28+49C→T ht, hm i-28 Afrikaner 18 I1350L 4048A→C ht 29 UK 1 none 3` UTR+17G→A ht 3`UTR Afrikaner 2 Silent and neutral variants of ABCC6 An additional 27 variants, assumed to be neutral or silent, were identified in the course of the ABCC6 screening of our cohort of 24 South African PXE individuals (Table 3). Login to comment 92 ABCC6 p.Arg1268Gln ABCC6 p.Val614Ala ABCC6 p.Gly61Asp ABCC6 p.Ile319Val ABCC6 p.His632Gln ABCC6 p.Lys281Glu Six other variants (G61D, K281E, I319V, V614A, H632Q and R1268Q) resulted in amino acid changes but appeared not to segregate with the disease in PXE pedigrees and were therefore likely to be neutral. Login to comment 93 ABCC6 p.Arg1339Cys ABCC6 p.Gly61Asp Although variant G61D represents a significant amino acid change, this allele was found in an Afrikaner patient homozygous for the mutation R1339C and was therefore considered to be a neutral variant. Login to comment 94 ABCC6 p.Arg1339Cys It is noteworthy that one silent variant (IVS28+ 49C→T) co-segregated with the R1339C alleles, as it was found in very close proximity (76 bp) to the 4015C→T substitution responsible for the arginyl to cysteinyl change (Tables 1, 3). Login to comment 95 ABCC6 p.Arg1138Gln ABCC6 p.Tyr768* No variants were found to co-segregate with the two other founder alleles R1138Q and Y768X. Login to comment 100 ABCC6 p.Arg1339Cys Although 865-889del was not identified in the 34 chromosomes analysed in Afrikaner PXE patients, data from the present study and previous results (Le Saux et al. 2001) indicated that R1339C is disease-causing and represents the most prevalent founder mutation found to date among South African Afrikaners. Login to comment 101 ABCC6 p.Arg1339Cys From the presence of a single R1339C allele in our control panel of 54 apparently unrelated and unaffected Afrikaners, we cannot calculate an accurate estimate of prevalence of these founder mutations in the Afrikaner population, as a much larger cohort of Afrikaners will need to be screened. Login to comment 104 ABCC6 p.Arg1138Gln ABCC6 p.Arg1339Cys ABCC6 p.Tyr768* Discussion The present study describes the identification of three PXE disease alleles, R1339C, Y768X and R1138Q, which are associated with three conserved haplotypes (types I, II and III) and which account for 74% of the PXE disease alleles among South African Afrikaners. Login to comment