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. 2009 Jul;9(4):574-80.
doi: 10.1016/j.meegid.2009.02.010. Epub 2009 Mar 9.

A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian Susceptibility to Mycobacterial Diseases in European descendants

J Yancoski  1 , C Rocco, A Bernasconi, M Oleastro, L Bezrodnik, C Vrátnica, F Haerynck, S D Rosenzweig
Affiliations

A 475 years-old founder effect involving IL12RB1: a highly prevalent mutation conferring Mendelian Susceptibility to Mycobacterial Diseases in European descendants

J Yancoski et al. Infect Genet Evol. 2009 Jul.

Abstract

Mutations in IFNGR1, IFNGR2, IL12RB1, IL12B, STAT1 and NEMO result in a common clinical phenotype known as Mendelian Susceptibility to Mycobacterial Diseases (MSMD). Interleukin-12 receptor beta1 (IL-12Rbeta1) deficiency is the most common genetic etiology for MSMD. Known mutations affecting IL12RB1 are recessively inherited and are associated with null response to both IL-12 and IL-23. Mutation IL12RB1 1623_1624delinsTT was originally described in 5 families from European origin (2 from Germany; 1 from Cyprus, France and Belgium). Interestingly, this same mutation was found in an unexpectedly high prevalence among IL-12Rbeta1 deficient patients in Argentina: 5-out-of-6 individuals born to unrelated families carried this particular change. To determine whether mutation 1623_1624delinsTT represents a DNA mutational hotspot or a founder effect, 34 polymorphic markers internal or proximal to IL12RB1 were studied in the Argentinean and the Belgian patients. A common haplotype spanning 1.45-3.51Mb was shared by all chromosomes carrying mutation 1623_1624delinsTT, and was not detected on 100 control chromosomes. Applying a modified likelihood-based method the age of the most recent common ancestor carrying mutation 1623_1624delinsTT was estimated in 475 years (95% CI, 175-1275), which is the time when the Spaniards initiated the colonization of the Americas. Mutation 1623_1624delinsTT represents the first founder effect described on IL-12Rbeta1, the most frequently affected gene in MSMD, and affecting patients with European ancestors. The reason(s) behind the persistency of this mutation across multiple generations, its relative high prevalence, and any potential selective advantage are yet to be established.

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Figures

Figure 1
Figure 1
Mutated haplotype screening on control chromosomes (A) Gel electrophoresis of PvuII-digested exon 7 IL12RB1. The 3 digestion patterns found in the Control population are shown. A705 homozygosity (bold) ruled out the mutated haplotype. (B) Gel electrophoresis of HphI-digested exon 4 IL12RB1. The 2 possible digestion patterns found in the Control population are shown. G451 homozygosity (bold) ruled out the mutated haplotype
Figure 2
Figure 2
Extragenic markers recombination fraction estimation Known distances and linkage for polymorphic sites surrounding IL12RB1 locus (filled rhombi) are shown. Linkage estimation for the extragenic markers indicated on the graph was based on a robust regression method. The slope derived from the least squares method is also despicted, although it shows a poorer fit and a slight bias due to outlying observations.
See this image and copyright information in PMC

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