Autosomal recessive Diamond-Blackfan anemia: Identification of mutations in MCM2, SEMA7A, and FLNB

Monday, September 22, 2014 — Poster Session II
4:00 p.m. – 6:00 p.m.	FAES Academic Center	NHGRI	GEN-11

* FARE Award Winner

Authors

• K.A. O'Brien
• N.E. Seidel
• J.E. Farrar
• A. Vlachos
• NIH Intramural Sequencing Center
• S.M. Anderson
• X. An
• E. Atsidaftos
• H.L. Malech
• R.J. Arceci
• S.R. Ellis
• J.M. Lipton
• D.M. Bodine

Abstract

Diamond Blackfan anemia (DBA) is a rare, congenital bone marrow failure syndrome characterized by severe anemia. Approximately 65% of DBA patients have heterozygous mutations or deletions in ribosomal protein gene sequences, while the genetic cause of DBA in the remaining 35% of patients is unknown. We performed whole exome sequencing on DBA families that had no known mutations for DBA or copy number variants. We identified missense mutations in Mini Chromosome Maintenance Complex Component 2 (MCM2) in one family, Filamin B (FLNB) gene in a second family, and Semaphorin 7a (SEMA7A) in a third family. These findings represent the first autosomal recessive mutations identified in DBA patients. Knockdown of MCM2, FLNB, or SEMA7A in CD34+ progenitor cells resulted in reduced numbers of CD41-/CD235+ erythroid cells, indicating these genes play important roles in erythropoiesis. Knockdown of MCM2, FLNB, or SEMA7A in CD34+ progenitor cells plated in semi-solid medium, resulted in reduced formation of BFU-E, but not CFU-GM colonies, suggesting an erythroid-specific role for these genes. In conclusion, we have identified mutations in non-ribosomal protein genes MCM2, SEMA7A, and FLNB in DBA patients and demonstrated an important role for these gene products in erythropoiesis.

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