Exome sequencing reveals a thrombopoietin ligand mutation in a Micronesian family with autosomal recessive aplastic anemia
| Autor: | Sunil Abhyankar, Jianwen Fang, Irfan Saadi, Nathan R. Wilson, Adam J. Olm-Shipman, Syed K. Rafi, Rodrigo T. Calado, Brigitte Ganter, Majed Dasouki, L. Mike Furness |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
Male
Models Molecular genetic structures Protein Conformation Hematopoiesis and Stem Cells medicine.disease_cause Biochemistry Exon hemic and lymphatic diseases Missense mutation Exome Molecular Targeted Therapy Cloning Molecular Child Exome sequencing Cells Cultured Genetics Mutation Comparative Genomic Hybridization Anemia Aplastic hemic and immune systems Hematology Exons Middle Aged Pedigree Thrombopoietin Cystine Female Receptors Thrombopoietin Micronesia Protein Binding Adult Adolescent Genotype Immunology Molecular Sequence Data Mutation Missense Genes Recessive Biology Structure-Activity Relationship Young Adult Sequence Homology Nucleic Acid medicine Humans Aplastic anemia Allele Base Sequence HIBRIDIZAÇÃO Cell Biology medicine.disease Molecular biology eye diseases Amino Acid Substitution sense organs Sequence Alignment |
| Zdroj: | Repositório Institucional da USP (Biblioteca Digital da Produção Intelectual) Universidade de São Paulo (USP) instacron:USP |
| Popis: | We recently identified 2 siblings afflicted with idiopathic, autosomal recessive aplastic anemia. Whole-exome sequencing identified a novel homozygous missense mutation in thrombopoietin (THPO, c.112C>T) in both affected siblings. This mutation encodes an arginine to cysteine substitution at residue 38 or residue 17 excluding the 21-amino acid signal peptide of THPO receptor binding domain (RBD). THPO has 4 conserved cysteines in its RBD that form 2 disulfide bonds. Our in silico modeling predicts that introduction of a fifth cysteine may disrupt normal disulfide bonding to cause poor receptor binding. In functional assays, the mutant-THPO–containing media shows two- to threefold reduced ability to sustain UT7-TPO cells, which require THPO for proliferation. Both parents and a sibling with heterozygous R17C change have reduced platelet counts, whereas a sibling with wild-type sequence has normal platelet count. Thus, the R17C partial loss-of-function allele results in aplastic anemia in the homozygous state and mild thrombocytopenia in the heterozygous state in our family. Together with the recent identification of THPO receptor (MPL) mutations and the effects of THPO agonists in aplastic anemia, our results have clinical implications in the diagnosis and treatment of patients with aplastic anemia and highlight a role for the THPO-MPL pathway in hematopoiesis in vivo. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|