Two founder mutations in the SEC23B gene account for the relatively high frequency of CDA II in the Italian population

Abstract

Congenital Dyserythropoietic Anemia type II is an autosomal recessive disorder characterized by unique abnormalities in the differentiation of cells of the erythroid lineage. The vast majority of CDA II cases result from mutations in the SEC23B gene. To date, 53 different causative mutations have been reported in 86 unrelated cases (from the CDA II European Registry), 47 of them Italian. We have now identified SEC23B mutations in 23 additional patients, 17 Italians and 6 non-Italian Europeans. The relative allelic frequency of the mutations was then reassessed in a total of 64 Italian and 45 non-Italian unrelated patients. Two mutations, E109K and R14W, account for over one-half of the cases of CDA II in Italy. Whereas the relative frequency of E109K is similar in Italy and in the rest of Europe (and is also prevalent in Moroccan Jews), the relative frequency of R14W is significantly higher in Italy (26.3% vs. 10.7%). By haplotype analysis we demonstrated that both are founder mutations in the Italian population. By using the DMLE+ program our estimate for the age of the E109K mutation in Italian population is ≈2,200 years; whereas for the R14W mutation it is ≈3,000 years. We hypothesize that E109K may have originated in the Middle East and may have spread in the heyday of the Roman Empire. Instead, R14W may have originated in Southern Italy. The relatively high frequency of the R14W mutation may account for the known increased prevalence of CDA II in Italy.

Figure 1

Allelic frequency of the mutations. The chart shows the results of the analysis performed on 10 mutations (E109K, R14W, R701C, R497C, R217X, R79X, A524V, R264X, R339X, R535X) shared between two cohorts. The allelic frequency has been assessed on 118 alleles from Italian cases and 84 from those not Italian.

Figure 2

SNP markers localization upstream and downstream E109K and R14W mutations. The chromosomal region containing the SEC23B gene is shown. Arrows indicate the distances of SNP markers from the location of the SEC23B mutation. Names of SNP markers are shown on the bars, whose height is shown to scale with the MAF. Distances in kb of SNP markers from both mutations, E109K and R14W, are highlighted in gray and black, respectively. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]

Figure 3

R14W and E109K age estimation. Age estimation of SEC23B R14W (A) and E109K (B) mutations. The posterior probability plots of the mutations age (in generations), as estimated by the software DMLE+2.3. The analyses were performed according to growth rate (r) of Italian populations. The vertical lines represent the average age values that had the highest probability (peak). The average 95% credible set (CS) of values for each posterior density is shown.

Figure 4

Dissemination of the E109K mutation in the Mediterranean area. The map shows the empire's greatest and largest territory in the year of 116 AD, around the time of Caesar Augustus (63 BC–14 AD) [The map is modified from a picture covered by Copyright AskRickToday.Com]. The dashed black arrows indicate the hypothetical migratory movements that led to the spread of the mutation in the Mediterranean area. Dots indicate the geographical areas in which the E109K mutation first occurred. [Color figure can be viewed in the online issue, which is available at wileyonlinelibrary.com.]