c-mpl mutations are the cause of congenital amegakaryocytic thrombocytopenia

Abstract

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare disease presenting with isolated thrombocytopenia in infancy and developing into a pancytopenia in later childhood. Thrombopoietin (TPO) is the main regulator of thrombocytopoiesis and has also been demonstrated to be an important factor in early hematopoiesis. We analyzed 9 patients with CAMT for defects in TPO production and reactivity. We found high levels of TPO in the sera of all patients. However, platelets and hematopoietic progenitor

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

“…While the maternally inherited mutation was previously reported [2,5], to our knowledge, the G to A transition at nucleotide 578 in exon 4 leading to a cysteine to tyrosine replacement, inherited from the patient's father, is a novel 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].…”

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.…”

Multivariate QTL linkage analysis suggests a QTL for platelet count on chromosome 19q

“…While mutations in the genes for thrombopoietin and the thrombopoietin receptor are known to produce clinical pathology (eg Congenital Amegakaryocytic Thrombocytopenia, Essential Thrombocythemia), the present results suggest that other regions of the genome may be more important in determining variation in platelet count amongst healthy adolescent twins. 37,38 In most positions along the genome the multivariate analyses (ie Multivariate test I and Multivariate test II) did not increase the power to detect linkage relative to the univariate results. This was perhaps surprising given that several theoretical papers have documented a clear advantage of multivariate approaches in the power to detect QTLs.…”