BACKGROUND: Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene. METHODS: Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion. RESULTS: The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5-16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22). CONCLUSION: Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.
BACKGROUND: Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene. METHODS: Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion. RESULTS: The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5-16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22). CONCLUSION: Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age.
Authors: Nischay K Rege; Ming Liu; Balamurugan Dhayalan; Yen-Shan Chen; Nicholas A Smith; Leili Rahimi; Jinhong Sun; Huan Guo; Yanwu Yang; Leena Haataja; Nelson F B Phillips; Jonathan Whittaker; Brian J Smith; Peter Arvan; Faramarz Ismail-Beigi; Michael A Weiss Journal: J Biol Chem Date: 2020-01-31 Impact factor: 5.157
Authors: David Carmody; Soo-Young Park; Honggang Ye; Marie E Perrone; G Alkorta-Aranburu; Heather M Highland; Craig L Hanis; Louis H Philipson; Graeme I Bell; Siri Atma W Greeley Journal: J Med Genet Date: 2015-06-22 Impact factor: 6.318
Authors: Intza Garin; Guiomar Perez de Nanclares; Elena Gastaldo; Lorna W Harries; Oscar Rubio-Cabezas; Luis Castaño Journal: PLoS One Date: 2012-01-03 Impact factor: 3.240
Authors: Lucas S de Santana; Lilian A Caetano; Aline D Costa-Riquetto; Pedro C Franco; Renata P Dotto; André F Reis; Letícia S Weinert; Sandra P Silveiro; Marcio F Vendramini; Flaviene A do Prado; Giovanna C P Abrahão; Ana Gregória F P de Almeida; Maria da G Rodrigues Tavares; Wagner Rodrigo B Gonçalves; Augusto C Santomauro Junior; Bruno Halpern; Alexander A L Jorge; Marcia Nery; Milena G Teles Journal: Mol Genet Genomic Med Date: 2019-10-08 Impact factor: 2.183