title: A founder mutation in the MPL gene causes congenital amegakaryocytic thrombocytopenia (CAMT) in the Ashkenazi Jewish population.
abstract: Congenital amegakaryocytic thrombocytopenia (MIM #604498) (CAMT) is a rare inherited disease presenting as severe thrombocytopenia in infancy. Untreated, many CAMT patients develop aplastic anemia within the first decade of life; the only effective treatment of CAMT is bone marrow transplantation. CAMT is the result of the presence of homozygous or compound heterozygous mutations in the thrombopoietin receptor-encoding gene, MPL. We report here the identification and characterization of a founder mutation in MPL in the Ashkenazi Jewish (AJ) population. This mutation, termed c.79+2T>A, is a T to A transversion in the invariant second base of the intron 1 donor splice site. Analysis of a random sample of 2018 individuals of AJ descent revealed a carrier frequency of approximately 1 in 75. Genotyping of six loci adjacent to the MPL gene in the proband and in the 27 individuals identified as carriers of the c.79+2T>A mutation revealed that the presence of this mutation in the AJ population is due to a single founder. The observed carrier frequency predicts an incidence of CAMT in the AJ population of approximately 1 in 22,500 pregnancies. The identification of this mutation will enable population carrier testing and will facilitate the identification and treatment of individuals homozygous for this mutation.
authors.affiliation: Bonei Olam, Center for Rare Jewish Genetic Disorders, 1755 46th St., Brooklyn, NY 11204, USA. cgjalas@boneiolam.org
authors.forename: Chaim
authors.initials: C
authors.lastname: Jalas
authors.forename: Sylvia L
authors.initials: SL
authors.lastname: Anderson
authors.forename: Tova
authors.initials: T
authors.lastname: Laufer
authors.forename: Kristina
authors.initials: K
authors.lastname: Martimucci
authors.forename: Alex
authors.initials: A
authors.lastname: Bulanov
authors.forename: Xie
authors.initials: X
authors.lastname: Xie
authors.forename: Josef
authors.initials: J
authors.lastname: Ekstein
authors.forename: Berish Y
authors.initials: BY
authors.lastname: Rubin
mesh_terms: D000483:Alleles; D001483:Base Sequence; D000080984:Congenital Bone Marrow Failure Syndromes; D018703:Founder Effect; D006239:Haplotypes; D006579:Heterozygote; D006801:Humans; D007231:Infant, Newborn; D007585:Jews / Q000235:genetics; D008297:Male; D009154:Mutation / Q000235:genetics*; D053628:Receptors, Thrombopoietin / Q000235:genetics*; D013921:Thrombocytopenia / Q000235:genetics*
chemical_list: D053628:Receptors, Thrombopoietin; C082218:MPL protein, human