Dysferlin and other non-red cell proteins accumulate in the red cell membrane of Diamond-Blackfan Anemia patients.
Diamond Blackfan Anemia (DBA) is a congenital anemia usually caused by diverse mutations in ribosomal proteins. Although the genetics of DBA are well characterized, the mechanisms that lead to macrocytic anemia remain unclear. We systematically analyzed the proteomes of red blood cell membranes from multiple DBA patients to determine whether abnormalities in protein translation or erythropoiesis contribute to the observed macrocytosis or alterations in the mature red blood cell membrane. In depth proteome analysis of red cell membranes enabled highly reproducible identification and quantitative comparisons of 1100 or more proteins. These comparisons revealed clear differences between red cell membrane proteomes in DBA patients and healthy controls that were consistent across DBA patients with different ribosomal gene mutations. Proteins exhibiting changes in abundance included those known to be increased in DBA such as fetal hemoglobin and a number of proteins not normally found in mature red cell membranes, including proteins involved in the major histocompatibility complex class I pathway. Most striking was the presence of dysferlin in the red blood cell membranes of DBA patients but absent in healthy controls. Immunoblot validation using red cell membranes isolated from additional DBA patients and healthy controls confirmed a distinct membrane protein signature specific to patients with DBA.
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Esther N
EN
Pesciotta
The Center for Systems and Computational Biology and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America ; Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Sira
S
Sriswasdi
The Center for Systems and Computational Biology and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America.
Hsin-Yao
HY
Tang
The Center for Systems and Computational Biology and Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania, United States of America ; Genomics and Computational Biology Graduate Group, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
David W
DW
Speicher
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America.
Philip J
PJ
Mason
Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, United States of America ; Department of Internal Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, United States of America.
Monica
M
Bessler
D000293:Adolescent; D000328:Adult; D029503:Anemia, Diamond-Blackfan / Q000097:blood* / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D000073939:Dysferlin; D004910:Erythrocyte Membrane / Q000378:metabolism*; D005260:Female; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism*; D009124:Muscle Proteins / Q000378:metabolism*; D040901:Proteomics; D015203:Reproducibility of Results; D055815:Young Adult
C114839:DYSF protein, human; D000073939:Dysferlin; D008565:Membrane Proteins; D009124:Muscle Proteins