Exome Sequencing Identifies Autosomal-Dominant SRP72 Mutations Associated with Familial Aplasia and Myelodysplasia Michael Kirwan, Amanda J. Walne, Vincent.

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Exome Sequencing Identifies Autosomal-Dominant SRP72 Mutations Associated with Familial Aplasia and Myelodysplasia Michael Kirwan, Amanda J. Walne, Vincent Plagnol, Mark Velangi, Aloysius Ho, Upal Hossain, Tom Vulliamy, Inderjeet Dokal The American Journal of Human Genetics Volume 90, Issue 5, Pages 888-892 (May 2012) DOI: 10.1016/j.ajhg.2012.03.020 Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 1 Heterozygous SRP72 Mutations Found in Two Families with Autosomal-Dominant Familial Aplastic Anemia and Myelodysplasia (A) Pedigrees of the two families. The index case in each family is indicated by an arrow. Black symbols represent MDS; blue symbols, AA or pancytopenia. A plus sign indicates a wild-type allele; a minus sign indicates a mutant allele. The index case (II-1) in family 1 was found to have pancytopenia (hemoglobin [Hb] 11.2 g/dl, white blood cell [WBC] count 1.9 × 109/l, neutrophils 0.7 × 109/l, platelets 93 × 109/l) when she was admitted for abdominal pain in 2006 at 14 years of age. The bone marrow biopsy showed reduced cellularity without significant dysplasia and normal cytogenetics. The mother (I-2) of the index case was also found to be pancytopenic, but her BM had features of dysplasia. Her two younger brothers (II-2, 12 years old and II-3, 11 years old) were also found to be pancytpenic (II-2, Hb 12.3 g/dl, WBC 1.7 × 109/l, neutrophils 0.7 × 109/l, platelets 113 × 109/l; II-3, Hb 12.6 g/dl, WBC 2.1 × 109/l, neutrophils 0.5 × 109/l, platelets 120 × 109/l). The four affected members in this family have not required any treatment for the hematological abnormalities. The index case (II-2) in Family 2 was found to have thrombocytopenia and macrocytic anemia at 33 years of age (1987). A BM biopsy in 1993 (at 39 years of age) showed her to have trilineage dysplasia, and the trephine had a cellularity of 40%. The bone marrow karyotype showed no abnormalities. Her blood count in 2006 (at 52 years of age) showed Hb 12.3 g/dl, mean corpuscular volume (MCV) 103fl, WBC 4.6 × 109/l, and platelets 70 x109/l. The index case's mother (I-2) had been diagnosed as having MDS for several years. In 2006 (at 76 years of age) her blood count was Hb 8.2 g/dl, WBC 4.9 × 109/l, and platelets 22 × 109/l. Both affected cases in family 2 have not had any specific treatment for the hematological abnormalities. (B) Example sequence traces showing wild-type (upper) and mutant (lower) sequences. The left panels show the 2 bp heterozygous CA deletion. The right panels show the heterozygous single-base G>A substitution. (C) Schematic showing where the amino acid alterations lie with regard to prominent domains within SRP72. The nine predicted TPR protein-protein interaction domains are shown in blue and numbered; the 7SL RNA binding domain is depicted in red. Approximate amino acid coordinates are indicated. The American Journal of Human Genetics 2012 90, 888-892DOI: (10.1016/j.ajhg.2012.03.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 2 Production of EGPF-SRP72 Fusion Protein in Mammalian Cells (A) Western blot showing EGFP-SRP72 fusion proteins including wild-type and variant SRP72 sequences. Endogenous SRP72 was detected with the same antibody but at a much lower level than exogenous protein, requiring a separate, longer exposure time. Approximate molecular weights (in kDa) are indicated. (B) HEK293 and rat NRK cells were transfected with the EGFP-SRP72 constructs, and the EGFP was visualized by fluorescence microscopy. The ER was costained red with ER-Tracker Red. Wild-type SRP72 shows greater coincidence with the ER than either of the variant SRP72 proteins in both cell types, suggesting that the variant SRP72 proteins are not localizing correctly within the cell. The American Journal of Human Genetics 2012 90, 888-892DOI: (10.1016/j.ajhg.2012.03.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions

Figure 3 PCR Quantitation of 7SL RNA Coprecipitated from HEK293 Cells Transfected with Wild-Type and Mutant EGFP-SRP72 Constructs (A) Standard PCR of a ∼200 bp fragment representing the 7SL RNA cDNA (B) Quantitative real-time PCR with a fluorescent primer/probe assay. Quantitative results are shown as levels relative to those obtained by coprecipitation with the wild-type construct. An EGFP-only and a mock transfection were included as negative controls, and a nonimmunoprecipitated HEK293 lysate was included as a positive control. (C) Quantitative real-time PCR results normalized to contaminating levels of the housekeeping gene ABL1. The result for the positive control is greatly reduced as a result of the higher levels of ABL1 in a raw cell lysate compared to one that has been depleted by coimmunoprecipitation. Error bars represent SEM from triplicate samples. The American Journal of Human Genetics 2012 90, 888-892DOI: (10.1016/j.ajhg.2012.03.020) Copyright © 2012 The American Society of Human Genetics Terms and Conditions