Open AccessIdentification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia
Author(s) -
Kenji Ihara,
Eiichi Ishii,
M. Eguchi,
Hidetoshi Takada,
Aiko Suminoe,
Robert A. Good,
Toshiro Hara
Publication year - 1999
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.96.6.3132
Subject(s) - thrombopoietin , exon , mutation , genetics , gene , biology , thrombopoietin receptor , compound heterozygosity , point mutation , microbiology and biotechnology , stem cell , haematopoiesis
Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disorder expressed in infancy and characterized by isolated thrombocytopenia and megakaryocytopenia with no physical anomalies. Our previous hematological analysis indicated similarities between human CAMT and murinec-mpl (thrombopoietin receptor) deficiency. Because thec-mpl gene was considered as one of the candidate genes for this disorder, we analyzed the genomic sequence of thec-mpl gene of a 10-year-old Japanese girl with CAMT. We detected two heterozygous point mutations: a C-to-T transition at the cDNA nucleotide position 556 (Q186X) in exon 4 and a single nucleotide deletion of thymine at position 1,499 (1,499 delT) in exon 10. Both mutations were predicted to result in a prematurely terminated c-Mpl protein, which, if translated, lacks all intracellular domains essential for signal transduction. Each of the mutations was segregated from the patient’s parents. Accordingly, the patient was a compound heterozygote for two mutations of thec-mpl gene, each derived from one of the parents. The present study suggests that at least a certain type of CAMT is caused by thec-mpl mutation, which disrupts the function of thrombopoietin receptor.