title: The genomic architecture of the PROS1 gene underlying large tandem duplication mutation that causes thrombophilia from hereditary protein S deficiency.
abstract: Hereditary protein S deficiency from a mutation in the PROS1 gene causes a genetic predisposition to develop venous thromboembolic disorders in humans. Recently, the acknowledgment of the clinical significance of large copy number mutations in protein S deficiency has increased. In this study, the authors investigated the genomic architecture of PROS1 in order to understand the microscopic sequence environment leading to large intragenic copy number mutations in the gene. The study subjects were 3 unrelated male patients with hereditary protein S deficiency from a tandem duplication mutation involving exons 5-10 of PROS1. Breakpoint analyses revealed 10-bp microhomology sequences in the intervening sequence (IVS)-4 and IVS-10 at the duplication junction without additional sequence changes, suggesting a single replication-based event as the potential molecular mechanism of rearrangement and founder effect in the mutant alleles. Further analyses on nucleotide sequences flanking the microhomology sequence revealed the presence of a repeat element (LTR-ERV1) and quadruplex-forming G-rich sequences in IVS-4. The results from genotyping multi-allelic short tandem repeats supported founder effect in the identical mutations in the 3 unrelated patients. In conclusion, we identified unique genomic architectures in the intervening sequences of PROS1 that underlie a large intragenic tandem duplication mutation leading to inherited thrombophilia.
authors.affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 135-710, Republic of Korea.
authors.forename: Ja Young
authors.initials: JY
authors.lastname: Seo
authors.affiliation: Samsung Biomedical Research Institute, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Ki-O
authors.initials: KO
authors.lastname: Lee
authors.affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 135-710, Republic of Korea.
authors.forename: Sun-Hee
authors.initials: SH
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, School of Medicine, CHA University, Seongnam, Republic of Korea.
authors.forename: Doyeun
authors.initials: D
authors.lastname: Oh
authors.affiliation: Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea; Cardiac & Vascular Center, Samsung Medical Center, Seoul, Republic of Korea.
authors.forename: Duk-Kyung
authors.initials: DK
authors.lastname: Kim
authors.affiliation: Department of Laboratory Medicine & Genetics, Samsung Medical Center, Sungkyunkwan University School of Medicine, 81 Irwon-ro, Gangnam-Gu, Seoul 135-710, Republic of Korea; Cardiac & Vascular Center, Samsung Medical Center, Seoul, Republic of Korea. Electronic address: heejinkim@skku.edu.
authors.forename: Hee-Jin
authors.initials: HJ
authors.lastname: Kim
mesh_terms: D000328:Adult; D001483:Base Sequence; D001798:Blood Proteins / Q000235:genetics*; D016022:Case-Control Studies; D056905:Chromosome Breakpoints; D020440:Gene Duplication; D015894:Genome, Human; D006801:Humans; D007438:Introns; D008297:Male; D008969:Molecular Sequence Data; D017293:Protein S; D018455:Protein S Deficiency / Q000235:genetics*; D020080:Tandem Repeat Sequences
chemical_list: D001798:Blood Proteins; C523390:PROS1 protein, human; D017293:Protein S
keywords: Breakpoint analyses; Copy number mutation; Genomic architecture; Inherited thrombophilia; PROS1