title: Exome sequencing identifies MPL as a causative gene in familial aplastic anemia.
abstract: The primary cause of aplastic anemia remains unknown in many patients. The aim of this study was to clarify the genetic cause of familial aplastic anemia. Genomic DNA of an affected individual from a multiplex consanguineous family was hybridized to a Nimblegen exome library before being sequenced on a GAIIx genome analyzer. Once the disease causing homozygous mutation had been confirmed in the consanguineous family, this gene was then analyzed for mutation in 33 uncharacterized index cases of aplastic anemia (<13 years) using denaturing HPLC. Abnormal traces were confirmed by direct sequencing. Exome sequencing identified a novel homozygous nonsense mutation in the thrombopoietin receptor gene MPL. An additional novel homozygous MPL mutation was identified in the screen of 33 aplastic anemia patients. This study shows for the first time a link between homozygous MPL mutations and familial aplastic anemia. It also highlights the important role of MPL in trilineage hematopoiesis.
authors.affiliation: Centre for Paediatrics, Blizard Institute of Cell and Molecular Science, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, 4 Newark Street, London, UK. a.walne@qmul.ac.uk
authors.forename: Amanda J
authors.initials: AJ
authors.lastname: Walne
authors.forename: Arran
authors.initials: A
authors.lastname: Dokal
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Richard
authors.initials: R
authors.lastname: Beswick
authors.forename: Michael
authors.initials: M
authors.lastname: Kirwan
authors.forename: Josu
authors.initials: J
authors.lastname: de la Fuente
authors.forename: Tom
authors.initials: T
authors.lastname: Vulliamy
authors.forename: Inderjeet
authors.initials: I
authors.lastname: Dokal
mesh_terms: D000741:Anemia, Aplastic / Q000235:genetics*; D002675:Child, Preschool; D003241:Consanguinity; D059472:Exome; D005190:Family; D005260:Female; D005838:Genotype; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D010375:Pedigree; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D017422:Sequence Analysis, DNA; D016615:Telomere
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human