RRC ID 66849
Author Nagamachi A, Kanai A, Nakamura M, Okuda H, Yokoyama A, Shinriki S, Matsui H, Inaba T.
Title Multiorgan failure with abnormal receptor metabolism in mice mimicking Samd9/9L syndromes.
Journal J Clin Invest
Abstract Autosomal dominant sterile α motif domain containing 9 (Samd9) and Samd9L (Samd9/9L) syndromes are a large subgroup of currently established inherited bone marrow failure syndromes that includes myelodysplasia, infection, growth restriction, adrenal hypoplasia, genital phenotypes, and enteropathy (MIRAGE), ataxia pancytopenia, and familial monosomy 7 syndromes. Samd9/9L genes are located in tandem on chromosome 7 and have been known to be the genes responsible for myeloid malignancies associated with monosomy 7. Additionally, as IFN-inducible genes, Samd9/9L are crucial for protection against viruses. Samd9/9L syndromes are caused by gain-of-function mutations and develop into infantile myelodysplastic syndromes associated with monosomy 7 (MDS/-7) at extraordinarily high frequencies. We generated mice expressing Samd9LD764N, which mimic MIRAGE syndrome, presenting with growth retardation, a short life, bone marrow failure, and multiorgan degeneration. In hematopoietic cells, Samd9LD764N downregulates the endocytosis of transferrin and c-Kit, resulting in a rare cause of anemia and a low bone marrow reconstitutive potential that ultimately causes MDS/-7. In contrast, in nonhematopoietic cells we tested, Samd9LD764N upregulated the endocytosis of EGFR by Ship2 phosphatase translocation to the cytomembrane and activated lysosomes, resulting in the reduced expression of surface receptors and signaling. Thus, Samd9/9L is a downstream regulator of IFN that controls receptor metabolism, with constitutive activation leading to multiorgan dysfunction.
Volume 131(4)
Published 2021-2-15
DOI 10.1172/JCI140147
PII 140147
PMID 33373325
PMC PMC7880413
MeSH Animals Chromosome Deletion Chromosomes, Human, Pair 7 / genetics Chromosomes, Human, Pair 7 / metabolism Disease Models, Animal ErbB Receptors / genetics ErbB Receptors / metabolism* Gain of Function Mutation* Humans Intracellular Signaling Peptides and Proteins / genetics Intracellular Signaling Peptides and Proteins / metabolism Mice Mice, Transgenic Myeloproliferative Disorders / genetics Myeloproliferative Disorders / metabolism* Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / genetics Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases / metabolism Syndrome Tumor Suppressor Proteins / genetics Tumor Suppressor Proteins / metabolism*
IF 11.864
Human and Animal Cells 293(RCB1637) 293T(RCB2202)