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1.
Nat Genet ; 45(5): 542-545, 2013 May.
Article in English | MEDLINE | ID: mdl-23563608

ABSTRACT

The blood group Vel was discovered 60 years ago, but the underlying gene is unknown. Individuals negative for the Vel antigen are rare and are required for the safe transfusion of patients with antibodies to Vel. To identify the responsible gene, we sequenced the exomes of five individuals negative for the Vel antigen and found that four were homozygous and one was heterozygous for a low-frequency 17-nucleotide frameshift deletion in the gene encoding the 78-amino-acid transmembrane protein SMIM1. A follow-up study showing that 59 of 64 Vel-negative individuals were homozygous for the same deletion and expression of the Vel antigen on SMIM1-transfected cells confirm SMIM1 as the gene underlying the Vel blood group. An expression quantitative trait locus (eQTL), the common SNP rs1175550 contributes to variable expression of the Vel antigen (P = 0.003) and influences the mean hemoglobin concentration of red blood cells (RBCs; P = 8.6 × 10(-15)). In vivo, zebrafish with smim1 knockdown showed a mild reduction in the number of RBCs, identifying SMIM1 as a new regulator of RBC formation. Our findings are of immediate relevance, as the homozygous presence of the deletion allows the unequivocal identification of Vel-negative blood donors.


Subject(s)
Blood Group Antigens/genetics , Erythrocyte Membrane/metabolism , Erythrocytes/immunology , Gene Deletion , Homozygote , Membrane Proteins/genetics , Quantitative Trait Loci , Alleles , Animals , Biomarkers/metabolism , Blood Group Antigens/immunology , Blood Group Antigens/metabolism , Electrophoretic Mobility Shift Assay , Erythrocytes/metabolism , Erythrocytes/pathology , Exome/genetics , Female , Gene Expression Profiling , Gene Regulatory Networks , Humans , Isoantibodies/immunology , Membrane Proteins/immunology , Membrane Proteins/metabolism , Molecular Sequence Data , Oligonucleotide Array Sequence Analysis , Pregnancy , Zebrafish/genetics
2.
Nat Genet ; 44(4): 435-9, S1-2, 2012 Feb 26.
Article in English | MEDLINE | ID: mdl-22366785

ABSTRACT

The exon-junction complex (EJC) performs essential RNA processing tasks. Here, we describe the first human disorder, thrombocytopenia with absent radii (TAR), caused by deficiency in one of the four EJC subunits. Compound inheritance of a rare null allele and one of two low-frequency SNPs in the regulatory regions of RBM8A, encoding the Y14 subunit of EJC, causes TAR. We found that this inheritance mechanism explained 53 of 55 cases (P < 5 × 10(-228)) of the rare congenital malformation syndrome. Of the 53 cases with this inheritance pattern, 51 carried a submicroscopic deletion of 1q21.1 that has previously been associated with TAR, and two carried a truncation or frameshift null mutation in RBM8A. We show that the two regulatory SNPs result in diminished RBM8A transcription in vitro and that Y14 expression is reduced in platelets from individuals with TAR. Our data implicate Y14 insufficiency and, presumably, an EJC defect as the cause of TAR syndrome.


Subject(s)
Genetic Predisposition to Disease , RNA-Binding Proteins/genetics , Thrombocytopenia/genetics , Upper Extremity Deformities, Congenital/genetics , 5' Untranslated Regions/genetics , Adolescent , Adult , Amino Acid Sequence , Animals , Base Sequence , Child , Child, Preschool , Congenital Bone Marrow Failure Syndromes , Female , Genetic Variation , Humans , Infant , Infant, Newborn , Male , Mutation , Platelet Count , Polymorphism, Single Nucleotide , Radius/abnormalities , Sequence Alignment , Sequence Analysis, DNA , Thrombocytopenia/congenital , Young Adult , Zebrafish/genetics
3.
Nat Genet ; 43(8): 735-7, 2011 Jul 17.
Article in English | MEDLINE | ID: mdl-21765411

ABSTRACT

Gray platelet syndrome (GPS) is a predominantly recessive platelet disorder that is characterized by mild thrombocytopenia with large platelets and a paucity of α-granules; these abnormalities cause mostly moderate but in rare cases severe bleeding. We sequenced the exomes of four unrelated individuals and identified NBEAL2 as the causative gene; it has no previously known function but is a member of a gene family that is involved in granule development. Silencing of nbeal2 in zebrafish abrogated thrombocyte formation.


Subject(s)
Blood Platelets/metabolism , Cytoplasmic Granules/metabolism , Gray Platelet Syndrome/genetics , Nerve Tissue Proteins/genetics , Secretory Vesicles/metabolism , Adult , Aged , Animals , Animals, Genetically Modified , Base Sequence , Blood Platelets/pathology , Embryo, Nonmammalian/cytology , Embryo, Nonmammalian/metabolism , Female , Gene Expression Regulation, Developmental , Humans , Male , Middle Aged , Molecular Sequence Data , Nerve Tissue Proteins/antagonists & inhibitors , Pedigree , Sequence Analysis, DNA , Sequence Homology, Nucleic Acid , Young Adult , Zebrafish/growth & development , Zebrafish/metabolism
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