A novel <i>SLC37A4</i> missense mutation in GSD‐Ib without hepatomegaly causes enhanced leukocytes endoplasmic reticulum stress and apoptosis

Xu, Qianyun; Tang, Haiyan; Duan, Liping; Zuo, Xiaoxia; Shi, Xiaoliu; Li, Yisha; Zhao, Hongjun; Zhang, Huali

doi:10.1002/mgg3.1568

Cited by 1 publication

(1 citation statement)

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“…Based on observations in primary patient samples, studies mainly aimed at the role of the unfolded protein response (UPR) and increased apoptosis in ELANE-mutant myeloid progenitor cells as the cause of neutropenia [36][37][38]. Because evidence for an elevated UPR was also obtained in other genetic subtypes of congenital neutropenia, this is considered a common albeit not a universal patho-mechanism of neutropenia [7,9,39,40]. However, not all ELANE mutations result in protein misfolding, leaving room for alternative explanations as to how ELANE mutations affect neutrophil development [41].…”

Section: Induced Pluripotent Stem Cell Modelsmentioning

confidence: 99%

Congenital neutropenia: disease models guiding new treatment strategies

Touw¹

2021

Current Opinion in Hematology

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Purpose of review Myeloid diseases are often characterized by a disturbed regulation of myeloid cell proliferation, survival, and maturation. This may either result in a severe paucity of functional neutrophils (neutropenia), an excess production of mature cells (myeloproliferative disorders) or in clonal expansions of dysplastic or immature myeloid cells (myelodysplasia and acute myeloid leukemia). Although these conditions can be regarded as separate entities, caused by the accumulation of distinct sets of somatic gene mutations, it becomes increasingly clear that they may also evolve as the prime consequence of a congenital defect resulting in severe neutropenia. Prominent examples of such conditions include the genetically heterogeneous forms of severe congenital neutropenia (SCN) and Shwachman-Diamond Syndrome. CSF3 treatment is a successful therapy to alleviate neutropenia in the majority of these patients but does not cure the disease nor does it prevent malignant transformation. Allogeneic stem cell transplantation is currently the only therapeutic option to cure SCN, but is relatively cumbersome, e.g., hampered by treatment-related mortality and donor availability. Hence, there is a need for new therapeutic approaches. Recent findings Developments in disease modeling, amongst others based on induced pluripotent stem cell and CRISPR/Cas9 based gene-editing technologies, have created new insights in disease biology and possibilities for treatment. In addition, they are fueling expectations for advanced disease monitoring to prevent malignant transformation. Summary This review highlights the recent progress made in SCN disease modeling and discusses the challenges that are still ahead of us to gain a better understanding of the biological heterogeneity of the disease and its consequences for patient care.

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