title: Nucleotide substitutions in CD101, the human homolog of a diabetes susceptibility gene in non-obese diabetic mouse, in patients with type 1 diabetes.
abstract: OBJECTIVE
  Although genome-wide association studies have identified more than 50 susceptibility genes for type 1 diabetes, low-frequency risk variants could remain unrecognized. The present study aimed to identify novel type 1 diabetes susceptibility genes by newly established methods.
  
  
  METHODS
  We carried out whole-exome sequencing and genome-wide copy-number analysis for a Japanese family consisting of two patients with type 1 diabetes and three unaffected relatives. Further mutation screening was carried out for 127 sporadic cases. The functional consequences of identified substitutions were evaluated by in silico analyses and fluorescence-activated cell sorting of blood samples.
  
  
  RESULTS
  Whole-exome sequencing and genome-wide copy-number analysis of familial cases showed co-segregation of the p.V863L substitution in CD101, the human homolog of an autoimmune diabetes gene in the non-obese diabetic mouse, with type 1 diabetes. Mutation screening of CD101 in 127 sporadic cases detected the p.V678L and p.T944R substitutions in two patients. The p.V863L, p.V678L and p.T944R substitutions were absent or extremely rare in the general population, and were assessed as 'probably/possibly damaging' by in silico analyses. CD101 expression on monocytes, granulocytes and myeloid dendritic cells of mutation-positive patients was weaker than that of control individuals.
  
  
  CONCLUSIONS
  These results raise the possibility that CD101 is a susceptibility gene for type 1 diabetes.
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.
authors.forename: Misako
authors.initials: M
authors.lastname: Okuno
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Kanazawa University, Kanazawa, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Kasahara
authors.affiliation: Department of Human Genetics, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Onodera
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Juntendo University, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Takubo
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Kanazawa University, Kanazawa, Japan.
authors.forename: Michiko
authors.initials: M
authors.lastname: Okajima
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, National Hospital Organization Mie Hospital, Tsu, Japan.
authors.forename: Shigeru
authors.initials: S
authors.lastname: Suga
authors.affiliation: Department of Human Genetics, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Watanabe
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.
authors.forename: Junichi
authors.initials: J
authors.lastname: Suzuki
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.
authors.forename: Tadayuki
authors.initials: T
authors.lastname: Ayabe
authors.affiliation: Department of Pediatrics, Nihon University School of Medicine, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Urakami
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Osaka City University, Osaka, Japan.
authors.forename: Tomoyuki
authors.initials: T
authors.lastname: Kawamura
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Yokohama City Minato Red Cross Hospital, Yokohama, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kikuchi
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Division of Pediatric Endocrinology and Metabolism, Shikoku Medical Center for Children and Adults, Zentsuji, Japan.
authors.forename: Ichiro
authors.initials: I
authors.lastname: Yokota
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Saitama Medical University, Saitama, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Kikuchi
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Saitama Medical University, Saitama, Japan.
authors.forename: Shin
authors.initials: S
authors.lastname: Amemiya
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Nakabayashi
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Keiko
authors.initials: K
authors.lastname: Hayashi
authors.affiliation: Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Hata
authors.affiliation: Department of Institute Director, National Research Institute for Child Health and Development, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.affiliation: Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.
authors.forename: Maki
authors.initials: M
authors.lastname: Fukami
authors.affiliation: The Japanese Study Group of Insulin Therapy for Childhood and Adolescent Diabetes, Kanazawa, Japan.|Department of Pediatrics, Tokyo Women's Medical University Medical Center East, Tokyo, Japan.
authors.forename: Shigetaka
authors.initials: S
authors.lastname: Sugihara
mesh_terms: D000293:Adolescent; D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D044466:Asian People; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics*; D051379:Mice; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D000073359:Exome Sequencing
chemical_list: D015703:Antigens, CD; C093213:CD101 antigen, human; D008562:Membrane Glycoproteins
keywords: Disease susceptibility; Exome; Mutation