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Nat Genet. 2016 Jul;48(7):792-7. doi: 10.1038/ng.3569. Epub 2016 May 16.

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

Author information

1
Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
2
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
3
Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
4
Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Japan.
5
Division of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.
6
Department of Pathology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
7
Department of Endocrinology and Metabolism, Fukuoka Children's Hospital and Medical Center for Infectious Diseases, Fukuoka, Japan.
8
Division of Pediatrics, Okinawa Prefectural Chubu Hospital, Okinawa, Japan.
9
Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
10
Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
11
Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
12
Division of Neonatology, Gunma Children's Medical Center, Gunma, Japan.
13
Department of Pediatrics, Hirosaki University Graduate School of Medicine, Aomori, Japan.
14
Department of Pediatrics, Ohdate Municipal Hospital, Ohdate, Japan.
15
Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
16
Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
17
Department of Neonatology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
18
Department of Pediatrics, Children's Medical Center, Yokohama City University Medical Center, Yokohama, Japan.
19
Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan.
20
Department of Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
21
Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
22
Laboratory of Gene Medicine, Keio University School of Medicine, Tokyo, Japan.
23
Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
24
Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.
25
Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.

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.

PMID:
27182967
DOI:
10.1038/ng.3569
[Indexed for MEDLINE]

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