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Origin of the prevalent SFTPB indel g.1549C > GAA (121ins2) mutation causing surfactant protein B (SP‐B) deficiency
Author(s) -
Tredano Mohammed,
Cooper David N.,
Stuhrmann Manfred,
Christodoulou John,
Chuzhanova Nadia A.,
RoudotThoraval Françoise,
Boëlle PierreYves,
Elion Jacques,
Jeanpierre Marc,
Feingold Josué,
Couderc Rémy,
Bahuau Michel
Publication year - 2005
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.31050
Subject(s) - indel , genetics , haplotype , indel mutation , biology , locus (genetics) , allele , linkage disequilibrium , gene , mutation , mutant , single nucleotide polymorphism , genotype
The SFTPB gene indel g.1549C > GAA (121ins2) accounts for about 2/3 of the mutant alleles underlying complete surfactant protein B deficiency. It is unclear, however, whether its prevalence is due to recurrent mutation or a founder effect. The underlying mutational mechanism was therefore sought through the analysis of local DNA sequence complexity. A relatively complex two‐step process was proposed: the first step involving slipped mispairing mediated by a direct repeat and generating an AGAA micro‐insertion, the second step involving hairpin loop resolution resulting in a CA micro‐deletion. The possibility of a founder effect was then assessed by typing 8 intragenic SNPs in 17 independent 121ins2 chromosomes from 10 probands, with parental non‐121ins2 chromosomes serving as controls. The 121ins2 chromosomes were assigned to three discrete haplotypes, whilst control chromosomes were distributed between 10 of the 11 observed parental haplotypes. The 121ins2 mutation was in strong and significant linkage disequilibrium (LD) with the tightly linked marker g.1580T/C (|D'| = 1; P ≈ 0.024), although only moderate LD was found with the rest of the locus (|D'| ≈ 0.54; P ≈ 0.136). Data on haplotype structure and the locus LD pattern, obtained from 81 independent Western‐European chromosomes, were consistent with the three mutation‐bearing haplotypes having originated from a common ancestor by recombination. Interestingly, all families harboring the 121ins2 indel had ancestors from a region of Northwestern Europe populated by Frankish/Saxon migration. Taken together, these data are consistent with the view that an indel mutation occurred on a relatively common SFTPB haplotype and now accounts for the majority of (and possibly all) extant 121ins2 chromosomes. © 2005 Wiley‐Liss, Inc.