Journal Article

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

Hara, Toshiro, Fukuzawa, Ryuji, Ihara, Kenji, Yamada, Shiro, Inoue, Hirosuke, Kitagawa, Yosuke, Adachi, Masanori, Toyoshima, Katsuaki, Kenmochi, Manabu, Narumi, Satoshi, Shimizu, Atsushi, Hasegawa, Tomonobu, Kitajima, Hiroyuki, Kudoh, Jun, Okano, Hideyuki, Hamada, Hiroyuki, Kohno, Miyuki, Kinjo, Saori, Fukami, Maki, Miyako, Kenichi, Shibata, Shinsuke, Ishii, Tomohiro, Kihara, Minako, Miyake, Noriko, Amano, Naoko, Urano, Hironaka, Okutani, Takahiro, Miyawaki, Masakazu, Matsumoto, Naomichi, Kinjo, Tadamune, Shiga, Kentaro, Yamaguchi, Tetsuya, Ohga, Shouichi, Higa, Asumi, Tanaka, Yukichi, Tsugawa, Koji, Kizaki, Zenro, Katsumata, Noriyuki, Muroya, Koji

2016

Overview

Satoshi Narumi, Tomonobu Hasegawa and colleagues describe a new adrenal hypoplasia syndrome termed MIRAGE that is caused by mutations in the endosome fusion facilitator SAMD9 . They find that patients with these mutations have severe growth restriction phenotypes, and they observe adaptation by aneuploidy, where there is accompanying protective loss of mutation-carrying chromosome 7. 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.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 13/106 / 14/28 / 45/23 / 45/61 / 45/70 / 692/308/2056 / 692/699/2743/1279 / 96/63 / 96/95 / Access control / Adolescent / Adrenal Insufficiency - genetics / Adrenal Insufficiency - pathology / Agriculture / Animal Genetics and Genomics / Biomedicine / Cancer Research / Child / Chromosomes / Chromosomes, Human, Pair 7 - genetics / Consortia / Endosomes - metabolism / ErbB Receptors - genetics / Female / Gene Function / Gene mutations / Genes / Genomes / Genotype / Grants / Growth Disorders - genetics / Growth Disorders - pathology / Health aspects / Histology / Human Genetics / Humans / Hypoadrenocorticism, Familial / Infant / Infant, Newborn / letter / Male / Middle Aged / Mutation / Mutation - genetics / Myelodysplastic Syndromes - genetics / Myelodysplastic Syndromes - pathology / Patients / Pedigree / Phenotype / Proteins / Proteins - genetics / R&D / Research & development / Science / Studies