Rare disease + lots of sequencing = mechanism?

In the age of DNA next-generation sequencing, we have come to take for granted the availability of a prodigious amount of data that seemingly sheds light upon disease. However, the reams of sequences that are often produced exceed our ability to understand the biological relevance and the disparate disease states associated with those data. Researchers often make descriptive observations that incorporate hematologic data, but we are sometimes left wanting for the mechanisms involved. In this issue of Blood, Frey et al have elucidated the mechanism of the vacuolar protein sorting 45 homolog (VPS45)–Rab GTPase axis, which impacts the biology of embryogenesis and causes congenital neutropenia and myelofibrosis.¹ 

Over the years, the Frey group has annotated numerous mutant genes associated with neutropenia and has followed the science wherever it leads. Herein, Frey et al have provided an elegant study that explains the epistasis seen among the partners of the complex, as observed by microscopy as well as biochemically in the protein level regulation of the composite partners and as suggested by previously reported observations on an isolated family pedigree.² 

Furthermore, their study supports the notion of how defects on each end of the developmental axis can be manifested because of a genetic mutation. Paradoxically, neutropenia that results from defects in trafficking of the granulocyte colony-stimulating factor receptor is empirically associated with differentiation defects, yet VPS45 and Rab gene mutations that result in severe defects with embryonic lethality in the mouse model have the likelihood for hypomorphic expression needed for reported clinical cases.

It is perhaps not so surprising that defects in VPS45-Rab result in a wide-ranging phenotype, given the observed defects in endocytic trafficking. Fascinatingly, it is not only the effect of differentiation that seems to give rise to neutrophil effects. Inherent defects in the neutrophils themselves with respect to phagosome processing suggest a wider-ranging defect in innate immunity.³  Given the implications for endosomes across the immune system,⁴  the phenotype of VPS45-Rab protein dysfunction in adaptive immunity needs to be investigated.

With the occurrence of severe neurocognitive defects seen in VPS45-Rab protein dysfunction with hematologic abnormalities, the effects of dependent endosomal function in neurologic pathways also need to be determined.⁵  Again, the empirical basis for such work is evident, because axonal transport of critical proteins is necessary for early growth and development. Ironically, the most obvious phenotypic and cursory findings for VPS45-Rab protein dysfunction provide a window for understanding how pervasive this pathway is for nonhematopoietic and hematopoietic functions alike. Equally so is the unlikely insight such work opens to common diseases of the elderly such as Parkinson disease and Alzheimer disease.⁶  VPS45-Rab complexes figure prominently in their pathogeneses, and endosomes are discretely noted microscopically in diseased neurons.

Although a defect in a basic process that leads to early embryonic death has been empirically observed, it is not clear why that defect can have such specificity in its effects in, for example, granulopoiesis. Why do patients with these defects not exhibit a low platelet count or anemia rather than simply neutropenia? If embryonic lethality occurs, then why is late differentiation also affected? The association with myelofibrosis has long been observed, yet a connection to leukemia is less than obvious. The more common genetic associations of MPN gene mutations, such as JAK2, MPL, and CALR, make biological sense with respect to signal transduction pathways,⁷  but endosome trafficking does not fit neatly into this paradigm. Conversely, cell stress and forced stem cell proliferation are thought to play a role in the increased leukemia predisposition of even generic aplastic anemia,⁸  not to mention the inherited bone marrow failure syndromes, such as Fanconi anemia, dyskeratosis congenita, and Diamond-Blackfan anemia.⁹  Thus, convergence on the health of the stem cell may be the true common denominator, no matter what the underlying cause is.

The lessons learned from a rare genetic disorder provide an important link, but there is still an incomplete picture of the pathway for understanding how stress, development, and specificity in hematopoiesis can lead to profound implications for health. Information gained from rare genetic diseases continues to provide unexpected insights and fulfills the age-old promise of the fruits of its investigation.