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Background: Gain-of-function of ATP-sensitive K + (K ATP ) channels because of mutations in the genes encoding SUR1 (ABCC8) or Kir6.2 (KCNJ11) is a major cause of neonatal diabetes mellitus (NDM). Our aim is to determine molecular defects in K ATP channels caused by ABCC8 mutations in Asian Indian children with NDM by in vitro functional studies., Methods: Wild-type (WT; NM_000352.4) or mutant sulfonylurea receptor 1 (SUR1) and Kir6.2 were co-expressed in COSm6 cells. Biogenesis efficiency and surface expression of mutant channels were assessed by immunoblotting and immunostaining. The response of mutant channels to cytoplasmic ATP and ADP was assessed by inside-out patch-clamp recordings. The response of mutant channels to known K ATP inhibitors in intact cells were determined by 86 Rb efflux assays., Results: Five SUR1 missense mutations, D212Y, P254S, R653Q, R992C, and Q1224H, were studied and showed increased activity in MgATP/MgADP. Two of the mutants, D212Y and P254S, also showed reduced response to ATP 4- inhibition, as well as markedly reduced surface expression. Moreover, all five mutants were inhibited by the K ATP channel inhibitors glibenclamide and carbamazepine., Conclusions: The study shows the mechanisms by which five SUR1 mutations identified in Asian Indian NDM patients affect K ATP channel function to cause the disease. The reduced ATP 4- sensitivity caused by the D212Y and P254S mutations in the L0 of SUR1 provides novel insight into the role of L0 in channel inhibition by ATP. The results also explain why sulfonylurea therapy is effective in two patients and inform how it should be effective for the other three patients., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The population of India is composed of many thousands of subpopulations, divided by geography, language, religion and caste or biraderi (patrilineage) boundaries, with endogamous marriage the norm. The net effect has been the creation of multiple genetic isolates with individual mutation profiles, but to date the clinical consequences of this highly complex differentiation have been largely ignored. In contrast, the topic of consanguinity continues to attract attention among medical and population geneticists, clinicians and social scientists. The significant progress made in India in improving childhood nutritional status and combating infectious disease means that genetic disorders have assumed ever-increasing importance. In populations where consanguineous marriage is widely practised, recessive genetic disorders will continue to gain greater prominence in the overall spectrum of ill health. At the same time this increase will in part be negated by urbanization and the move to smaller family sizes, which predictably will result in a decline in the prevalence of consanguineous unions. Developing an understanding of these changes will require a wide-ranging and multidisciplinary investigative approach for which community genetics is ideally suited.

An attempt is made to enumerate the effects of some factors on hypohaptoglobinaemia in a sample of 389 infants (along with their mothers) who were classified electrophoretically for haptoglobins (Hp). 85 . 5% of infants were Hp 0-0. There was no direct effect of birth-weight on the frequency of Hp 0-0 but there was a significant interaction between maternal haptoglobin type and birth-weight of newborn, showing an excess of 2-2 among mothers of low birth-weight babies, who were mostly Hp 0-0. Some trend towards reduced Hp 0-0 frequency among premature babies was discernible. There was a significant effect of parity on the frequency of detectable haptoglobin patterns among low birth-weight infants. An increase in the frequency of haptoglobin pattern was observed with increase in parity and birth-weight. The distributions of detectable haptoglobin patterns among newborn and mothers were similar. ABO incompatibility, sex, economic status and caste variation did not show any effects on the frequency of Hp 0-0.