Homologous recombination among three intragene Alu sequences causes an inversion-deletion resulting in the hereditary bleeding disorder glanzmann thrombasthenia

Journal Article · Thu Jul 01 00:00:00 EDT 1993 · American Journal of Human Genetics; (United States)

OSTI ID:5914746

Li, L; Bray, P F ^[1]

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1. Johns Hopkins Univ. Medical School, Baltimore, MD (United States)

The crucial role of the human platelet fibrinogen receptor in maintaining normal hemostasis is best exemplified by the autosomal recessive bleeding disorder Glanzmann thrombasthenia (GT). The platelet fibrinogen receptor is a heterodimer composed of glycoproteins IIb (GPIIb) and IIIa (GPIIIa). Platelets from patients with GT have a quantitative or qualitative abnormality in GPIIb and GPIIIa and can neither bind fibrinogen nor aggregate. Very few genetic defects have been identified that cause this disorder. The authors describe a kindred with GT in which the affected individuals have a unique inversion-deletion mutation in the gene for GPIIIa. Patient platelets lacked both GPIIIa protein and mRNA. Southern blots of patient genomic DNA probed with an internal 1.0-kb GPIIIa cDNA suggested a large rearrangement of this gene but were normal when probed with small GPIIIa cDNA fragments that were outside the mutation. Cytogenetics and pulsed-field gel analysis of the GPIIIa gene were normal, making a translocation or a very large rearrangement unlikely. Additional Southern analyses suggested that the abnormality was not a small insertion. The authors constructed a patient genomic DNA library and isolated fragments containing the 5' and 3' breakpoints of the mutation. The nucleotide sequence from these genomic clones was determined and revealed that, relative to the normal gene, the mutant allele contained a 1-kb deletion immediately preceding a 15-kb inversion. The DNA breaks occurred in two inverted and one forward Alu sequence within the gene for GPIIIa and in the left, right, and left arms, respectively, of these sequences. There was a 5-bp repeat at the 3 terminus of the inversion. One copy of the repeat remained in the mutant allele breakpoint junction. The alignment and orientation of the different Alu sequences, as well as the position of the breakpoints, suggest that the inversion preceded the deletion in this complex rearrangement. 41 refs., 5 figs.

• OSTI ID: 5914746
• Journal Information: American Journal of Human Genetics; (United States), Vol. 53:1; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
BLOOD PLATELETS
AGGLOMERATION
GLYCOPROTEINS
GENE MUTATIONS
HEMIC DISEASES
RECEPTORS
BLOOD COAGULATION
DNA SEQUENCING
FIBRINOGEN
GENE RECOMBINATION
MEMBRANE PROTEINS
BIOLOGICAL MATERIALS
BLOOD
BLOOD CELLS
BLOOD COAGULATION FACTORS
BODY FLUIDS
COAGULANTS
DISEASES
DRUGS
GLOBULINS
HEMATOLOGIC AGENTS
HEMOSTATICS
MATERIALS
MUTATIONS
ORGANIC COMPOUNDS
PROTEINS
STRUCTURAL CHEMICAL ANALYSIS
550400* - Genetics