Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of- Function Mutations in TXNL4A Causes Burn-McKeown Syndrome Dagmar Wieczorek,

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Compound Heterozygosity of Low-Frequency Promoter Deletions and Rare Loss-of- Function Mutations in TXNL4A Causes Burn-McKeown Syndrome Dagmar Wieczorek, William G. Newman, Thomas Wieland, Tea Berulava, Maria Kaffe, Daniela Falkenstein, Christian Beetz, Elisabeth Graf, Thomas Schwarzmayr, Sofia Douzgou, Jill Clayton-Smith, Sarah B. Daly, Simon G. Williams, Sanjeev S. Bhaskar, Jill E. Urquhart, Beverley Anderson, James O’Sullivan, Odile Boute, Jasmin Gundlach, Johanna Christina Czeschik, Anthonie J. van Essen, Filiz Hazan, Sarah Park, Anne Hing, Alma Kuechler, Dietmar R. Lohmann, Kerstin U. Ludwig, Elisabeth Mangold, Laura Steenpaß, Michael Zeschnigk, Johannes R. Lemke, Charles Marques Lourenco, Ute Hehr, Eva-Christina Prott, Melanie Waldenberger, Anne C. Böhmer, Bernhard Horsthemke, Raymond T. O’Keefe, Thomas Meitinger, John Burn, Hermann-Josef Lüdecke, Tim M. Strom The American Journal of Human Genetics Volume 95, Issue 6, Pages 698-707 (December 2014) DOI: 10.1016/j.ajhg.2014.10.014 Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 1 Pedigrees of Individuals with BMKS and Biallelic Mutations in TXNL4A (A) Family BMKS001 with two affected brothers (III/1 and III/2) with a maternally inherited promoter deletion and a paternally inherited frameshift mutation, p.Glu117∗ (previously published in Wieczorek et al.2). (B) Family BMKS002 with an affected male individual (II/1) carrying a maternal promotor deletion and a paternal frameshift mutation, p.Gln13∗. (C) Family BMKS004 with an affected female individual (II/1) carrying a promoter deletion on one and a 1.2 Mb terminal deletion 18q23 (chr18: 76,854,774_78,077,248del) on the other allele. Mother does not carry both deletions; father’s DNA is unavailable. (D) Family BMKS005 with an affected female individual (II/4) with a paternal promoter deletion and a maternal frameshift mutation, p.Val44Alafs∗48. (E) Family BMKS006 with an affected female individual (II/1) carrying a paternal promoter deletion and a large maternally inherited interstitial 18q deletion (chr18: 77,421,290_77,904,990del). (F) Family BMKS007 with two affected brothers (II/1 and II/2) carrying the maternal promoter deletion and a large terminal deletion 18q (chr18: 76,841,645_78,077,248del) (previously published in Burn et al.1). (G) Family BMKS009 with an affected female individual with a maternal promoter deletion and ring chromosome 18 resulting in a 18q deletion (chr18: 73,376,178_78,077,248del) (published in Burn et al.1). Paternal DNA was not available. (H) Family BMKS010 with an affected male individual with promoter deletion and single exon deletion 3. DNA was not available from both parents. The American Journal of Human Genetics 2014 95, 698-707DOI: (10.1016/j.ajhg.2014.10.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 2 Facial Phenotype of Individuals with BMKS (A and B) Persons III/1 and III/2 of family BMKS0013. (C and D) Person II/1 of family BMKS002. (E and F) Person II/1 of family BMKS004. (G and H) Person II/4 of family BMKS005. (I and J) Person II/1 of family BMKS006. (K and L) Persons II/1 and II/2 of family BMKS007. Note the craniofacial similarities including narrow palpebral fissures with coloboma of lower eyelids, high nasal bridge, short philtrum, small mouth, small chin, and large and protruding ears. (M and N) Person BMKS009 in adulthood with narrow and upslanting palpebral fissures, high nasal bridge, and short philtrum. Consent for the publication of photographs was obtained for these individuals. The American Journal of Human Genetics 2014 95, 698-707DOI: (10.1016/j.ajhg.2014.10.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 3 Gene Structure of TXNL4A with Identified Mutations and Deletions The heterozygous deletions comprising TXNL4A identified in the index individuals of families BMKS009, BMKS007, BMKS004, and BMKS006 with a size of 4.7 Mb, 1.147 Mb, 1.164 Mb, and 0.484 Mb, respectively, are shown at the top of the figure. The gene structure with the identified mutation in families BMKS001, BMKS002, and BMKS005 are shown at the bottom as well as the exon 3 deletion of family BMKS010. The American Journal of Human Genetics 2014 95, 698-707DOI: (10.1016/j.ajhg.2014.10.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 4 The 34 bp Deletion Reduces the Activity of the Putative TXNL4A Promoter in Dual Luciferase Assays HEK293 cells were transfected with the reporter vector carrying the wild-type promoter without the deletion (without del) of TXNL4A, with either type of the 34 bp deletion (type 1 Δ or type 2 Δ), or the reporter vector without insert (control). The vector without the deletion (magenta) functioned as promoter, enhancing the luciferase expression by 85-fold in comparison with the control vector (blue). However, the vector with the type 1 Δ (green) reduced promoter’s activity by 59% and with the type 2 Δ (red) by additional 13%, resulting in a total reduction of 72% in comparison with the vector without the deletion. Data represent the means and standard deviations of six technical replicates of three independent experiments and demonstrate the fold change of the relative luciferase units (RLU) compared to the control vector. Asterisks indicate statistically significant differences, with ∗p < 0.05 (Wilcoxon rank sum test). The American Journal of Human Genetics 2014 95, 698-707DOI: (10.1016/j.ajhg.2014.10.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions

Figure 5 Depletion of DIB1, the Yeast Ortholog of TXNL4A, Results in Defective Tri-snRNP Assembly Yeast whole-cell splicing extract from strain DIB1GALHA grown in galactose (nondepleted) or glucose (Dib1 depleted) was fractionated through a 10%–30% glycerol gradient to separate spliceosome complexes. RNA isolated from fractions was subjected to primer extension to detect the levels of the U1, U2, U4, U5, and U6 snRNAs in each fraction. The fraction numbers are indicated at the top of each panel. The locations of the U6 snRNP, U4/U6 di-snRNP, U5 snRNP, and U4/U6.U5 tri-snRNP in the fractions are indicated below each panel. The American Journal of Human Genetics 2014 95, 698-707DOI: (10.1016/j.ajhg.2014.10.014) Copyright © 2014 The American Society of Human Genetics Terms and Conditions