Poikiloderma with Neutropenia, Clericuzio Type (OMIM #604173): From USB1 RNA Biology to a Candidate Model of Compartmentalized Cyclic Nucleotide Signaling

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Abstract
Poikiloderma with neutropenia, Clericuzio type (PN; OMIM #604173), is a rare autosomal recessive genodermatosis caused by biallelic loss-of-function variants in U6 snRNA Biogenesis 1 (USB1), with approximately 100 molecularly confirmed cases. Beyond the defining post-inflammatory poikiloderma and non-cyclic neutropenia, affected individuals show recurrent sinopulmonary infection, impaired wound healing, tendon contractures, and primary gonadal failure in males. USB1 is a 2H-superfamily 3′ to 5′ exoribonuclease that removes oligoadenylate tails added by Poly(A) polymerase associated protein 5 (PAPD5) and PAPD7; its loss destabilizes guide-strand microRNAs and blocks the emergence of CD45+ hematopoietic progenitors. Splicing is not measurably disturbed in patient cells, so the earlier splicing-centered account requires revision. Drawing on previously unpublished endocrine, neurologic and imaging data from two affected brothers, we develop a candidate model in which the microRNA lesion reaches cyclic nucleotide signaling by two routes: de-repression of phosphodiesterase E3B (PDE3B) after loss of miR-142-5p, and loss of a perinuclear and Golgi cyclic AMP compartment after coordinate reduction in A-kinase anchoring protein 6 (AKAP6) and PDE4D interacting protein (PDE4DIP). We state where the model is supported, where it conflicts with published effects, and what would refute it, arguing for compartment-restricted dysregulation rather than global deficiency. PAPD5/7 inhibition, leading to repression of PDE3B, is closest to the causal lesion, but its on-target neurotoxicity makes it an experimental tool rather than a candidate drug.

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