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

doi:10.1038/ng.3569

. 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

Satoshi Narumi¹, Naoko Amano¹, Tomohiro Ishii¹, Noriyuki Katsumata², Koji Muroya³, Masanori Adachi³, Katsuaki Toyoshima⁴, Yukichi Tanaka⁵, Ryuji Fukuzawa⁶, Kenichi Miyako⁷, Saori Kinjo⁸, Shouichi Ohga^{9

10}, Kenji Ihara⁹, Hirosuke Inoue⁹, Tadamune Kinjo⁹, Toshiro Hara⁹, Miyuki Kohno¹¹, Shiro Yamada¹¹, Hironaka Urano¹², Yosuke Kitagawa¹³, Koji Tsugawa¹⁴, Asumi Higa¹⁵, Masakazu Miyawaki¹⁵, Takahiro Okutani¹⁵, Zenro Kizaki¹⁶, Hiroyuki Hamada¹⁶, Minako Kihara¹⁷, Kentaro Shiga¹⁸, Tetsuya Yamaguchi¹⁸, Manabu Kenmochi¹⁹, Hiroyuki Kitajima²⁰, Maki Fukami², Atsushi Shimizu²¹, Jun Kudoh²², Shinsuke Shibata^{23

24}, Hideyuki Okano²³, Noriko Miyake²⁵, Naomichi Matsumoto²⁵, Tomonobu Hasegawa¹

Affiliations

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.

PMID: 27182967
DOI: 10.1038/ng.3569

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

Satoshi Narumi et al. Nat Genet. 2016 Jul.

. 2016 Jul;48(7):792-7.

doi: 10.1038/ng.3569. Epub 2016 May 16.

Authors

Affiliations

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.

PMID: 27182967
DOI: 10.1038/ng.3569

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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[1] Leukemia. 2002 Sep;16(9):1865-6 - PubMed

[2] Leukemia. 2002 Sep;16(9):1865-6 - PubMed

[3] Nat Genet. 2005 Feb;37(2):166-70 - PubMed

[4] Nat Genet. 2005 Feb;37(2):166-70 - PubMed

[5] Nature. 1994 Dec 15;372(6507):672-6 - PubMed

[6] Nature. 1994 Dec 15;372(6507):672-6 - PubMed

[7] Blood. 2007 Dec 15;110(13):4385-95 - PubMed

[8] Blood. 2007 Dec 15;110(13):4385-95 - PubMed

[9] Am J Hum Genet. 2006 Oct;79(4):759-64 - PubMed

[10] Am J Hum Genet. 2006 Oct;79(4):759-64 - PubMed

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

Affiliations

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

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