Identification of mutations in the c-mpl gene in congenital amegakaryocytic thrombocytopenia

Abstract

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 murine c-mpl (thrombopoietin receptor) deficiency. Because the c-mpl gene was considered as one of the candidate genes for this disorder, we analyzed the genomic sequence of the c-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 the c-mpl gene, each derived from one of the parents. The present study suggests that at least a certain type of CAMT is caused by the c-mpl mutation, which disrupts the function of thrombopoietin receptor.

A hematopoietic growth factor, thrombopoietin, has a proapoptotic role in the brain

“…However, a temporal delay in neurotrophic selection may alter the final size of neuronal populations. We note that a mutation of the human TPOR͞Mpl1 gene, causing congenital amegakaryocytic thrombocytopenia, has also been associated with abnormal brain MRI findings (46). In mice, TPO and TPOR mutations are viable (1), but neurodevelopmental defects have not been analyzed.…”

The molecular and cellular biology of thrombopoietin: the primary regulator of platelet production

“…Recent studies have identi®ed homozygous elimination of c-MPL as causing a large number of cases of congenital amegakaryocytic thrombocytopenia (CAMT (Ihara et al, 1999;van den Oudenrijn et al, 2000;Ballmaier et al, 2001)). Infants with this disorder present with excessive bleeding in the perinatal period, although occasionally the diagnosis is delayed a short time.…”

Congenital amegakaryocytic thrombocytopenia—Report of a new c‐mpl gene missense mutation

“…The hallmark is absence of megakaryocytes [1], high serum thrombopoietin (tpo) levels, and in vitro megakaryocyte culture insensitivity to tpo stimulation [2]. CAMT is due to the germline mutations of both tpo receptor alleles, c-mpl [3][4][5]. c-mpl knock-out mice not only lack megakaryopoiesis but also have pluripotent stem cell defects [1].…”