Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude.

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Reccurrent F8 Intronic Deletion Found in Mild Hemophilia A Causes Alu Exonization Yohann Jourdy, Alexandre Janin, Mathilde Fretigny, Anne Lienhart, Claude Négrier, Dominique Bozon, Christine Vinciguerra The American Journal of Human Genetics Volume 102, Issue 2, Pages 199-206 (February 2018) DOI: 10.1016/j.ajhg.2017.12.010 Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 1 Identification of a c.2113+461_2113+473del Variation in the Two Index Case Subjects Two mRNA fragments were observed when amplifying fragments spanning exons 11–14 (wild-type 646 bp; mutant 768 bp). Sequencing of the 768 bp fragment found the insertion of intron 13 fragment of 122 bp (c.2113_2114ins2113+477_2113+598). Sequencing of the intron 13 found a c.2113+461_2113+473del short deletion in the poly(T)-tail of the right arm of antisense AluY. Abbreviations: M, marker size; WT, wild-type; Ex, exon, bp; base pair. The American Journal of Human Genetics 2018 102, 199-206DOI: (10.1016/j.ajhg.2017.12.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 2 Molecular Characterization of the Splicing Effect of c.2113+461_2113+473del HeLa (A) and Huh7 (B) cells were transiently transfected with wild-type (pTB2ex13WT) and mutated (pTB2ex13DEL) splicing reporter constructs. 48 hr after transfection, RNA products were analyzed by RT-PCR (normal exon 13 splicing 456 bp; AluY inclusion 578 bp). Lanes 1 to 3: pTB2ex13WT; lanes 4 to 6: pTB2ex13DEL. Abbreviations: M, marker size; bp, base pair. The American Journal of Human Genetics 2018 102, 199-206DOI: (10.1016/j.ajhg.2017.12.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 3 Substitutions in Poly(T) Tail Promote Inclusion of the AluY Exon (A) Schematic representation of the minigene including AluY exon (gray square), exon 13 (white square), intronic region (black lines). The wild-type sequence (pTB2ex13WT) as well as the mutated sequence (pTB2ex13WT_5mut) are depicted below. Point variations are highlighted in gray. The AluY exonized sequence is underlined. (B and C) RT-PCR results obtained after transfection of HeLa (B) or Huh7 (C) cells with pTB2ex13WT (lines 1 to 3) and pTB2ex13WT_5mut (lines 4 to 6). Abbreviations: Ex, exon; M, marker size; bp, base pair. The American Journal of Human Genetics 2018 102, 199-206DOI: (10.1016/j.ajhg.2017.12.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions

Figure 4 hnRNP C Repression Promotes Inclusion of the AluY Exon (A) Western blotting using the indicated antibodies after hnRNP C knockdown with siRNA (sihnRNP C) against control (siCont) in HeLa cells. (B) RT-PCR results obtained after transfection with pTB2ex13WT or pTB2ex13DEL minigenes in HeLa cells treated with the indicated siRNA. Abbreviations: M; marker size; bp, base pair. The American Journal of Human Genetics 2018 102, 199-206DOI: (10.1016/j.ajhg.2017.12.010) Copyright © 2017 American Society of Human Genetics Terms and Conditions