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. SUBJECTS: 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. CONCLUSION: 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.
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. SUBJECTS: 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. CONCLUSION: 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: James T Bennett; Valeria Vasta; Min Zhang; Jaya Narayanan; Peter Gerrits; Si Houn Hahn Journal: Mol Genet Metab Date: 2014-12-20 Impact factor: 4.797
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Authors: Maggie Shepherd; Beverley Shields; Suzanne Hammersley; Michelle Hudson; Timothy J McDonald; Kevin Colclough; Richard A Oram; Bridget Knight; Christopher Hyde; Julian Cox; Katherine Mallam; Christopher Moudiotis; Rebecca Smith; Barbara Fraser; Simon Robertson; Stephen Greene; Sian Ellard; Ewan R Pearson; Andrew T Hattersley Journal: Diabetes Care Date: 2016-06-06 Impact factor: 19.112
Authors: Binu M Paul; Mark B Consugar; Moonnoh Ryan Lee; Jamie L Sundsbak; Christina M Heyer; Sandro Rossetti; Vickie J Kubly; Katharina Hopp; Vicente E Torres; Eliecer Coto; Maurizio Clementi; Nadja Bogdanova; Edgar de Almeida; Daniel G Bichet; Peter C Harris Journal: Kidney Int Date: 2013-06-12 Impact factor: 10.612