Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2 Tommaso Pippucci,

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Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2 Tommaso Pippucci,

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Mutations in the 5′ UTR of ANKRD26, the Ankirin Repeat Domain 26 Gene, Cause an Autosomal-Dominant Form of Inherited Thrombocytopenia, THC2 Tommaso Pippucci, Anna Savoia, Silverio Perrotta, Núria Pujol-Moix, Patrizia Noris, Giovanni Castegnaro, Alessandro Pecci, Chiara Gnan, Francesca Punzo, Caterina Marconi, Samuele Gherardi, Giuseppe Loffredo, Daniela De Rocco, Saverio Scianguetta, Serena Barozzi, Pamela Magini, Valeria Bozzi, Luca Dezzani, Mariateresa Di Stazio, Marcella Ferraro, Giovanni Perini, Marco Seri, Carlo L. Balduini The American Journal of Human Genetics Volume 88, Issue 1, Pages 115-120 (January 2011) DOI: 10.1016/j.ajhg.2010.12.006 Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 1 Linkage to Chromosome 10p11.1-p12 in Four THC2 Families Segregation of microsatellite marker haplotypes in the THC2 locus on chromosome 10p11.1-p12 (with the corresponding Mb positions) in the two large THC2-linked families (Family 1 and 2) and in the two smaller families (families 3 and 4). Black symbols indicate affected individuals, and white symbols indicate healthy ones. Slashed symbols mean that those individuals are deceased. Only individuals for whom the corresponding haplotypes are reported were genotyped. Families 1 and 2, which carry the c.-128G>A and c.-127A>T mutations, respectively (Table 1), are consistent with linkage at the THC2 locus. Families 3 and 4 do not provide significant LOD scores, but their 10p11.1-p12 region segregates consistently with the disease. Family 3 carries the c.-118C>T mutation (Table 1). No mutation in ANKRD26 was found in the affected members of family 4, and therefore segregation of the haplotype is probably not related to the disease in this family. A 0/0 in the haplotype means unsuccessful genotyping for the marker in that individual. Haplotype representation was obtained with Haplopainter version 1.0.17 The American Journal of Human Genetics 2011 88, 115-120DOI: (10.1016/j.ajhg.2010.12.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 2 The 5′-UTR-Mutated Sequences of ANKRD26 (A) Alignment of the 5′ UTRs of orthologs from Homo sapiens (Hs: NM_014915.2), Macaca mulatta (Mm: XM_002808496.1), and Bos taurus (Bt: NM_001113767.1). Nucleotide changes are in bold. Stars indicate matching sites. (B) Electropherograms showing the six different heterozygous mutations identified in THC2 families (Table 1) . The American Journal of Human Genetics 2011 88, 115-120DOI: (10.1016/j.ajhg.2010.12.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions

Figure 3 Firefly/Renilla RLU Ratios, Normalized against Wild-Type, for Each of the 5′ UTR Variants in the Functional Study Scale bars represent means ± standard deviation. Corresponding values of each variant for – PMA/TPO Dami cells (light gray) and + PMA/TPO Dami cells (dark gray) are as follows: c.-106T>C—0.73 ± 0.16, 0.94 ± 0.19; c.-127A>T— 1.09 ± 0.26, 1.63 ± 0.91; c.-128G>A—1.83 ± 0.19, 3.37 ± 0.36; and c.-134G>A—1.84 ± 0.49, 2.79 ± 0.20. The assumption of homogeneity of variances was respected both in −PMA/TPO and in +PMA/TPO Dami (Levene's statistic > .13 and .36, respectively). Normality of the distribution was respected for all the samples (Kolmogorov-Smirnov Z Test). ANOVA rejected the null hypothesis of equality of means in both groups. Significant p values at the 5% level for a Dunnett's test against the c.-106T>C control are reported above the corresponding column of the histogram. The American Journal of Human Genetics 2011 88, 115-120DOI: (10.1016/j.ajhg.2010.12.006) Copyright © 2011 The American Society of Human Genetics Terms and Conditions