title: Patients of African ancestry with hemophagocytic lymphohistiocytosis share a common haplotype of PRF1 with a 50delT mutation.
abstract: Mutations of the perforin gene (PRF1) are present in a proportion of patients with hemophagocytic lymphohistiocytosis (HLH). We found that all identified infants with HLH of African descent (17 from USA, 4 from Europe) have 50delT-PRF1 (16 homozygotes, 5 compound heterozygotes), accounting for the most frequently observed PRF1 mutation. Two additional patients with HLH, self-reporting as Hispanic, carried 50delT, but no Caucasians were identified with 50delT. To test the hypothesis that this mutation represents a single haplotype, DNA from 23 patients with HLH and 30 African-American control subjects was sequenced for the PRF1 gene, including portions of the intron containing known single nucleotide polymorphisms (SNPs). The same groups were genotyped at 3 microsatellites proximal to PRF1. The SNP profiles of patients with 50delT-PRF1 were identical, and 5 novel SNPs were identified among African-American control subjects. Patients with 50delT-PRF1 were also found to have had an earlier age of disease onset than patients with other PRF1 mutations. Extent of haplotype sharing and variability of microsatellite alleles in 50delT-PRF1 chromosomes suggest that this mutation arose approximately 1000 to 4000 years ago and is restricted to patients of African descent.
authors.affiliation: Divisions of Hematology/Oncology and Human Genetics, Cincinnati Children's Hospital Medical Center and the Center for Genome Information, University of Cincinnati, Cincinnati, Ohio, USA. Susan.Lee@cchmc.org
authors.forename: Susan Molleran
authors.initials: SM
authors.lastname: Lee
authors.forename: Janos
authors.initials: J
authors.lastname: Sumegi
authors.forename: Joyce
authors.initials: J
authors.lastname: Villanueva
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Tabata
authors.forename: Kejian
authors.initials: K
authors.lastname: Zhang
authors.forename: Ranajit
authors.initials: R
authors.lastname: Chakraborty
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Sheng
authors.forename: Rita
authors.initials: R
authors.lastname: Clementi
authors.forename: Genevieve
authors.initials: G
authors.lastname: de Saint Basile
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Filipovich
mesh_terms: D044383:Black People / Q000235:genetics*; D016022:Case-Control Studies; D002648:Child; D002675:Child, Preschool; D005060:Europe; D006239:Haplotypes; D006630:Hispanic or Latino / Q000235:genetics; D006801:Humans; D007223:Infant; D051359:Lymphohistiocytosis, Hemophagocytic / Q000208:ethnology / Q000235:genetics*; D008562:Membrane Glycoproteins / Q000235:genetics*; D018895:Microsatellite Repeats; D009154:Mutation; D009820:Ohio; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D017422:Sequence Analysis, DNA; D001741:Black or African American
chemical_list: D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D054353:Perforin