SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7

S Narumi, N Amano, T Ishii, N Katsumata, K Muroya… - Nature …, 2016 - nature.com
S Narumi, N Amano, T Ishii, N Katsumata, K Muroya, M Adachi, K Toyoshima, Y Tanaka…
Nature genetics, 2016nature.com
Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new
form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia,
infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy)
syndrome. By exome sequencing and follow-up studies, we identified 11 patients with
adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9.
Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild …
Abstract
Adrenal hypoplasia is a rare, life-threatening congenital disorder. Here we define a new form of syndromic adrenal hypoplasia, which we propose to term MIRAGE (myelodysplasia, infection, restriction of growth, adrenal hypoplasia, genital phenotypes, and enteropathy) syndrome. By exome sequencing and follow-up studies, we identified 11 patients with adrenal hypoplasia and common extra-adrenal features harboring mutations in SAMD9. Expression of the wild-type SAMD9 protein, a facilitator of endosome fusion, caused mild growth restriction in cultured cells, whereas expression of mutants caused profound growth inhibition. Patient-derived fibroblasts had restricted growth, decreased plasma membrane EGFR expression, increased size of early endosomes, and intracellular accumulation of giant vesicles carrying a late endosome marker. Of interest, two patients developed myelodysplasitc syndrome (MDS) that was accompanied by loss of the chromosome 7 carrying the SAMD9 mutation. Considering the potent growth-restricting activity of the SAMD9 mutants, the loss of chromosome 7 presumably occurred as an adaptation to the growth-restricting condition.
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