Clinical and molecular characterization of neonatal diabetes and monogenic syndromic diabetes in Asian Indian children

Abstract

Mutations in the pancreatic ATP sensitive K(+) channel proteins [sulfonyluea receptor 1 (SUR1) and inward rectifier K(+) channel Kir6.2 (Kir6.2), encoded by ATP-binding cassette transporter subfamily C member 8 (ABCC8) and potassium channel J11 (KCNJ11), respectively], are the most common cause of neonatal diabetes. We describe the clinical presentation and molecular characterization of Asian Indian children with neonatal diabetes mellitus and monogenic syndromes of diabetes. We sequenced KCNJ11, ABCC8 and insulin (INS) genes in 33 unrelated Indian probands with onset of diabetes below one year of age. A total of 12 mutations were identified which included ABCC8 mutations in seven, KCNJ11 mutations in three and INS mutations in two children. The Asp212Tyr mutation in ABCC8 was novel. We also detected two novel mutations (Val67Met and Leu19Arg) in children with syndromic forms of diabetes like Berardinelli Seip syndrome [1-acyl-sn-glycerol-3-phosphate acyltransferase beta (AGPAT2)] and Fanconi Bickel syndrome [solute carrier family 2A2 (SLC2A2)]. Children carrying the KCNJ11 (Cys42Arg, Arg201Cys) and ABCC8 (Val86Ala, Asp212Tyr) mutations have been successfully switched over from insulin therapy to oral sulfonylurea. Our study is the first large genetic screening study of neonatal diabetes in India.

Functional characterization of activating mutations in the sulfonylurea receptor 1 ( ABCC8 ) causing neonatal diabetes mellitus in Asian Indian children

“…Here, we describe the structural and functional cause of heterozygous SUR1 ( ABCC8, NM_000352.4) mutations in five different genetically unrelated Asian Indian children associated with NDM or with some neurological features. Of the five mutations characterized in this study, two (D212Y and R653Q) have been previously reported by our group . The P254S mutation has been reported in an Indian patient by Flanagan et al The R992C and Q1224H mutations have not been reported in Asian Indian children so far.…”

Relapsing Transient Neonatal Diabetes Mellitus due to ABCC8 Mutation

“…In contrast to the western literature, Indian literature shows that Transient neonatal diabetes accounts only for 5% of all neonatal diabetes mellitus [5,6]. Chromosome 6q related mutations followed by ABCC8 (SUR) mutations and KCNJ11 account for most of TNDM.…”

“…Though transient in about 50% of children, diabetes recurs in the pediatric age group or in the early adult age group. Children in remission need to be followed up annually for hyperglycemia [6].…”

Precision Diabetes Is Slowly Becoming a Reality

“…This is an excellent illustration of precision diabetes and one of the most exciting clinical situations in diabetology. Switching a child aged just a few weeks or months to oral tablets, from what would otherwise have meant lifelong insulin injections, is nothing short of a miracle to the child and the family, and we have been able to help many such children [50]. …”