title: Comprehensive molecular analysis of Japanese patients with pediatric-onset MODY-type diabetes mellitus.
abstract: BACKGROUND
  In Asians, mutations in the known maturity-onset diabetes of the young (MODY) genes have been identified in only <15% of patients. These results were obtained mostly through studies on adult patients.
  
  
  OBJECTIVE
  To investigate the molecular basis of Japanese patients with pediatric-onset MODY-type diabetes.
  
  
  METHODS
  Eighty Japanese patients with pediatric-onset MODY-type diabetes.
  
  
  METHODS
  Mitochondrial 3243A>G mutation was first tested by the polymerase chain reaction restriction fragment length polymorphism analysis for maternally inherited families. Then, all coding exons and exon-intron boundaries of the HNF1A, HNF1B, GCK, and HNF4A genes were amplified from genomic DNA and directly sequenced. Multiplex ligation-dependent probe amplification analysis was also performed to detect whole-exon deletions.
  
  
  RESULTS
  After excluding one patient with a mitochondrial 3243A>G, mutations were identified in 38 (48.1%) patients; 18 had GCK mutations, 11 had HNF1A mutations, 3 had HNF4A mutations, and 6 had HNF1B mutations. In patients aged <8 yr, mutations were detected mostly in GCK at a higher frequency (63.6%). In patients >9 yr of age, mutations were identified less frequently (45.1%), with HNF1A mutations being the most frequent. A large fraction of mutation-negative patients showed elevated homeostasis model assessment (HOMA) insulin-resistance and normal HOMA-β indices. Most of the HNF1B mutations were large deletions, and, interestingly, renal cysts were undetectable in two patients with whole-gene deletion of HNF1B.
  
  
  CONCLUSIONS
  In Japanese patients with pediatric-onset MODY-type diabetes, mutations in known genes were identified at a much higher frequency than previously reported for adult Asians. A fraction of mutation-negative patients presented with insulin-resistance and normal insulin-secretory capacities resembling early-onset type 2 diabetes.
authors: Department of Pediatric Endocrinology and Metabolism, Children's Medical Center, Osaka City General Hospital, 2-13-22 Miyakojima-Hondori, Miyakojima, Osaka 534-0021, Japan. yorif@kuhp.kyoto-u.ac.jp
authors: Tohru
authors: T
authors: Yorifuji
authors: Rika
authors: R
authors: Fujimaru
authors: Yuki
authors: Y
authors: Hosokawa
authors: Nobuyoshi
authors: N
authors: Tamagawa
authors: Momoko
authors: M
authors: Shiozaki
authors: Katsuya
authors: K
authors: Aizu
authors: Kazuhiko
authors: K
authors: Jinno
authors: Yoshihiro
authors: Y
authors: Maruo
authors: Hironori
authors: H
authors: Nagasaka
authors: Toshihiro
authors: T
authors: Tajima
authors: Koji
authors: K
authors: Kobayashi
authors: Tatsuhiko
authors: T
authors: Urakami
mesh_terms: D000293:Adolescent; D017668:Age of Onset; D044466:Asian People / Q000235:genetics* / Q000706:statistics & numerical data; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis / Q000379:methods; D004272:DNA, Mitochondrial / Q000032:analysis / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics*; D005260:Female; D005787:Gene Frequency; D005941:Glucokinase / Q000235:genetics; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics; D051557:Hepatocyte Nuclear Factor 4 / Q000235:genetics; D006801:Humans; D007223:Infant; D008297:Male
chemical_list: D004272:DNA, Mitochondrial; C496487:HNF1A protein, human; C496495:HNF1B protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; D051539:Hepatocyte Nuclear Factor 1-beta; D005941:Glucokinase