In 2 members of a family with familial erythroleukemia (FERLK; 133180), Braunstein et al. (2016) identified a heterozygous c.4009G-A transition in the ERBB3 gene, resulting in an ala1337-to-thr (A1337T) substitution at a conserved residue near the C terminus. The mutation, which was found by whole-exome sequencing, was not found in the Exome Variant Server, but was found at a low frequency in the ExAC database (7 of 119,654 alleles). The variant was also found in an asymptomatic 63-year-old family member, indicating incomplete penetrance, as well as in a female family member who died from metastatic breast cancer, but did not have leukemia. The family had a significant history of various solid tumors. Expression of the mutation into murine pro-B cells (BaF3) and human hematopoietic progenitor cells caused a growth advantage and resulted in increased cellular proliferation compared to wildtype. However, the increased proliferation was observed only in the presence of ERBB2 (164870), NRG1B (see 142445), and EPO (133170), indicating that the growth was dependent on ligand binding and heterodimerization. Analysis of the cell cycle under these conditions showed a decrease in the G1 phase and an increase in the S and G2/M phase in cells carrying the mutation compared to controls. These findings suggested that the A1337T variant overcomes a G1 phase cell cycle block. Cells carrying the mutation also showed a block in erythroid differentiation compared to controls.
