A nonsense mutation in the DNA repair factor Hebo causes mild bone marrow failure and microcephaly

Inherited bone marrow failuresyndromes are human conditionsin which one or several cell lineages of the hemopoietic system are affected. They are present at birth or may develop progressively. They are sometimes accompanied by other developmental anomalies. Three main molecular causes have been recognized to result in bone marrow failuresyndromes: (1) defects in the Fanconi anemia(FA)/BRCA DNA repairpathway, (2) defects in telomere maintenance, and (3) abnormal ribosome biogenesis. We analyzed a patient with mild bone marrow failureand microcephalywho did not present with the typical FA phenotype. Cells from this patient showed increased sensitivity to ionizing radiations and phleomycin, attesting to a probable DNA double strand break (dsb) repair defect. Linkage analysis and whole exome sequencingrevealed a homozygous nonsense mutationin the ERCC6L2 gene. We identified a new ERCC6L2 alternative transcript encoding the DNA repairfactor Hebo, which is critical for complementation of the patient’s DNAdsb repair defect. Sequence analysis revealed three structured regions within Hebo: a TUDOR domain, an adenosine triphosphatasedomain, and a new domain, HEBO, specifically present in Hebo direct orthologues. Hebo is ubiquitously expressed, localized in the nucleus, and rapidly recruited to DNAdsb’s in an NBS1-dependent manner.