FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation Elfride De Baere, Diane Beysen, Christine.

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FOXL2 and BPES: Mutational Hotspots, Phenotypic Variability, and Revision of the Genotype-Phenotype Correlation Elfride De Baere, Diane Beysen, Christine Oley, Birgit Lorenz, Julie Cocquet, Paul De Sutter, Koen Devriendt, Michael Dixon, Marc Fellous, Jean-Pierre Fryns, Arturo Garza, Christoffer Jonsrud, Pasi A. Koivisto, Amanda Krause, Bart P. Leroy, Françoise Meire, Astrid Plomp, Lionel Van Maldergem, Anne De Paepe, Reiner Veitia, Ludwine Messiaen The American Journal of Human Genetics Volume 72, Issue 2, Pages 478-487 (February 2003) DOI: 10.1086/346118 Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 1 The predicted protein translations for FOXL2 mutations detected in this and previous studies are shown at the left and are assembled into groups. Groups A–D are predicted truncated proteins: A, without forkhead domain; B, with partial forkhead; C, with complete forkhead and without poly-Ala tract; D, with complete forkhead and poly-Ala domains. Group E comprises frameshift mutations leading to elongated proteins with complete forkhead and poly-Ala domains; group F, in-frame mutations; and group G, missense mutations. Vertical stripes indicate the forkhead domain, dark gray shows the poly-Ala tract, and diagonal stripes represent novel amino acids caused by a frameshift mutation. In the first column, the corresponding nucleotide changes are represented. The numbering is according to Crisponi et al. (2001). Mutations found in the present study are indicated in bold, and novel mutations are underlined. In the second column, the respective amino acid changes are shown. The two mutational hotspots demonstrated in the present study are boxed, and their percentages are shown at the right: 30% of the mutations lead to poly-Ala expansions, and 13% are a novel duplication 1080–1096dup17. Abbreviations: fs = frameshift; stop = stop codon. In the third column, the BPES type is shown (F1 = familial, type I; F2 = familial, type II; F1+2 = familial, occurrence of both BPES types in the same family; F = familial, type undetermined; S1 = sporadic, type I; and S = sporadic). The American Journal of Human Genetics 2003 72, 478-487DOI: (10.1086/346118) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 2 Pedigrees and respective FOXL2 mutations of patients with familial BPES, represented in accordance with the subdivision and numbering of figure 1. For patients with sporadic disease, no pedigree information is shown. Affected individuals are indicated by filled symbols; individuals tested are indicated by an asterisk below the symbol. SIDS = sudden infant death syndrome. Abbreviations: AU = Australia; BE = Belgium; DE = Germany; GB = United Kingdom; MX = Mexico. The American Journal of Human Genetics 2003 72, 478-487DOI: (10.1086/346118) Copyright © 2003 The American Society of Human Genetics Terms and Conditions

Figure 3 Explanation of the mechanism of the novel triplication 921–935trip15 by a replication error. Predictions of DNA hairpins are based on MFOLD (Walter et al. 1994). When the DNA polymerase is stalling because of the GC richness of the region, the sequences 1 and 2 of the newly synthesized strand form a DNA hairpin because they are self-complementary (structure 1). This allows the sequence 3 to hybridize with the template of the region 2, since they have exactly the same sequence, and this leads to a duplication of the underlined sequence (nt 921–935). Once this extra sequence is present (4), there may be a rearrangement of the hairpin, which leads to the formation of another one involving the sequences (single and double asterisk). The formation of the second hairpin is favorable, because it is more stable (by an energy excess of 1.5 kcal/mole; see structure 2). Finally, the 3′ end of the sequence 4 hybridizes with the template of sequence 2, which results in the triplication after escaping repair. Further, notice that sequences 1–4 form a very stable, almost perfect, hairpin (−28 kcal/mole). The American Journal of Human Genetics 2003 72, 478-487DOI: (10.1086/346118) Copyright © 2003 The American Society of Human Genetics Terms and Conditions