Molecular Characterization of a Novel 3' Mutation in RUNX1 in a New Pedigree with Familial Platelet Disorder.

Familial Platelet Disorder with Propensity to Acute Myelogenous Leukemia (FPD/AML; OMIM 601399) is a rare disorder with an autosomal dominant inheritance pattern characterized by varying degrees of thrombocytopenia, clinical bleeding due to platelet dysfunction, and an increased risk of developing myeloid malignancy. To date, twenty-six families with this disorder have been described and all carry germline RUNX1 mutations as the causative genetic abnormality. The spectrum of RUNX1 mutations includes point mutations within the RUNT domain and frameshift and termination mutations throughout the body of the gene. Here we report identification of a new family with FPD with a novel nonsense mutation resulting in premature protein termination at amino acid 388.

Our four generation pedigree includes a mother (II:4) diagnosed with dysplasia and normal karyotype acute myeloid leukemia now in remission after a matched sibling allogeneic stem cell transplant, and her daughter (III:2) with thrombocytopenia since childhood, excessive bleeding with childbirth, and 5q- syndrome diagnosed at 37 years old. Genomic DNA was obtained from all available family members, and RUNX1 cDNA (transcription variants a through c) was sequenced. In addition, RUNX1 cDNA was analyzed for second mutations in bone marrow samples from both patients at the time of diagnosis of their initial bone marrow malignancy.

RUNX1 sequencing of germline DNA revealed heterozygosity for a novel nonsense mutation in exon 8 (c.1163C>A), which is predicted to result in premature protein truncation (p.Ser388X). Full sequencing of RUNX1 cDNA from II:4's AML does not show any secondary mutations. Our current efforts include full sequencing of RUNX1 cDNA from III:2's bone marrow malignancy as well as functional studies of the truncated protein.

We have identified a novel 3' RUNX1 mutation within exon 8, which is predicted to result in premature protein truncation at amino acid 388. To date, this is the most distal mutation identified in an FPD/AML pedigree. The identification of this mutation suggests that the last 100 amino acids, which are known to contain the RUNX1 inhibition domain, contribute an essential function. Further characterization of this RUNX1 mutation and its encoded truncated protein may yield insight into RUNX1's role in leukemogenesis in FPD and de novo AML.

No relevant conflicts of interest to declare.