title: SAMD9 mutations cause a novel multisystem disorder, MIRAGE syndrome, and are associated with loss of chromosome 7.
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.
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Narumi
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Naoko
authors.initials: N
authors.lastname: Amano
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Ishii
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Katsumata
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Muroya
authors.affiliation: Department of Endocrinology and Metabolism, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Masanori
authors.initials: M
authors.lastname: Adachi
authors.affiliation: Department of Neonatology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Toyoshima
authors.affiliation: Division of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.
authors.forename: Yukichi
authors.initials: Y
authors.lastname: Tanaka
authors.affiliation: Department of Pathology, Tokyo Metropolitan Children's Medical Center, Tokyo, Japan.
authors.forename: Ryuji
authors.initials: R
authors.lastname: Fukuzawa
authors.affiliation: Department of Endocrinology and Metabolism, Fukuoka Children's Hospital and Medical Center for Infectious Diseases, Fukuoka, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Miyako
authors.affiliation: Division of Pediatrics, Okinawa Prefectural Chubu Hospital, Okinawa, Japan.
authors.forename: Saori
authors.initials: S
authors.lastname: Kinjo
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Department of Perinatal and Pediatric Medicine, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Shouichi
authors.initials: S
authors.lastname: Ohga
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Hirosuke
authors.initials: H
authors.lastname: Inoue
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Tadamune
authors.initials: T
authors.lastname: Kinjo
authors.affiliation: Department of Pediatrics, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kohno
authors.affiliation: Department of Pediatrics, Gunma University Graduate School of Medicine, Gunma, Japan.
authors.forename: Shiro
authors.initials: S
authors.lastname: Yamada
authors.affiliation: Division of Neonatology, Gunma Children's Medical Center, Gunma, Japan.
authors.forename: Hironaka
authors.initials: H
authors.lastname: Urano
authors.affiliation: Department of Pediatrics, Hirosaki University Graduate School of Medicine, Aomori, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Kitagawa
authors.affiliation: Department of Pediatrics, Ohdate Municipal Hospital, Ohdate, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Tsugawa
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Asumi
authors.initials: A
authors.lastname: Higa
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Masakazu
authors.initials: M
authors.lastname: Miyawaki
authors.affiliation: Department of Pediatrics, Wakayama Medical University, Wakayama, Japan.
authors.forename: Takahiro
authors.initials: T
authors.lastname: Okutani
authors.affiliation: Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
authors.forename: Zenro
authors.initials: Z
authors.lastname: Kizaki
authors.affiliation: Department of Pediatrics, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Hamada
authors.affiliation: Department of Neonatology, Japanese Red Cross Kyoto Daiichi Hospital, Kyoto, Japan.
authors.forename: Minako
authors.initials: M
authors.lastname: Kihara
authors.affiliation: Department of Pediatrics, Children's Medical Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Kentaro
authors.initials: K
authors.lastname: Shiga
authors.affiliation: Department of Pediatrics, Children's Medical Center, Yokohama City University Medical Center, Yokohama, Japan.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Yamaguchi
authors.affiliation: Department of Pediatrics, Kitasato University School of Medicine, Sagamihara, Japan.
authors.forename: Manabu
authors.initials: M
authors.lastname: Kenmochi
authors.affiliation: Department of Neonatal Medicine, Osaka Medical Center and Research Institute for Maternal and Child Health, Osaka, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kitajima
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: Division of Biomedical Information Analysis, Iwate Tohoku Medical Megabank Organization, Iwate Medical University, Iwate, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Shimizu
authors.affiliation: Laboratory of Gene Medicine, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Kudoh
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.|Electron Microscope Laboratory, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Shinsuke
authors.initials: S
authors.lastname: Shibata
authors.affiliation: Department of Physiology, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Okano
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan.
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.affiliation: Department of Pediatrics, Keio University School of Medicine, Tokyo, Japan.
authors.forename: Tomonobu
authors.initials: T
authors.lastname: Hasegawa
mesh_terms: D000293:Adolescent; D000309:Adrenal Insufficiency / Q000235:genetics* / Q000473:pathology; D002648:Child; D002897:Chromosomes, Human, Pair 7 / Q000235:genetics*; D011992:Endosomes / Q000378:metabolism; D066246:ErbB Receptors / Q000235:genetics; D005260:Female; D005838:Genotype; D006130:Growth Disorders / Q000235:genetics* / Q000473:pathology; D006801:Humans; D000075262:Hypoadrenocorticism, Familial; D007223:Infant; D007231:Infant, Newborn; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009190:Myelodysplastic Syndromes / Q000235:genetics* / Q000473:pathology; D010375:Pedigree; D010641:Phenotype; D011506:Proteins / Q000235:genetics*
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D011506:Proteins; C514443:SAMD9 protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors