Inherited human Apollo deficiency causes severe bone marrow failure and developmental defects
Abstract
Inherited bone marrow failure syndromes (IBMFS) represent a group of disorders typified by impaired production of one or several blood cell types. The telomere biology disorders dyskeratosis congenita (DC) and its severe variant Høyeraal-Hreidarsson (HH) syndrome are rare IBMFS characterized by bone marrow failure, developmental defects, and various premature aging complications associated with critically short telomeres. Here we identified biallelic variants in the gene encoding the 5'-to-3' DNA exonuclease Apollo/SNM1B in three unrelated patients presenting with a DC/HH phenotype consisting of early onset hypocellular bone marrow failure, B and NK lymphopenia, developmental anomalies, microcephaly and/or intrauterine growth retardation. All three patients carry a homozygous or compound heterozygous (in combination with a null-allele) missense variant affecting the same residue L142 (L142F or L142S) located in the catalytic domain of Apollo. Apollo-deficient cells from patients exhibited spontaneous chromosome instability and impaired DNA repair that was complemented by CRISPR/Cas9-mediated gene correction. Furthermore, patients' cells showed signs of telomere fragility that were however not associated with global reduction of telomere length. Unlike patients' cells, human Apollo KO HT1080-cell lines showed strong telomere dysfunction accompanied by excessive telomere shortening, suggesting that the L142S and L142F Apollo variants are hypomorphic. Collectively, these findings define human Apollo as a genome caretaker and identify biallelic Apollo variants as a genetic cause of a hitherto unrecognized severe IBMFS combining clinical hallmarks of DC/HH with normal telomere length.
Domains
Genetics| Origin | Publication funded by an institution |
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