Nature Genetics
19, 268 - 270 (1998)
doi:10.1038/953
Mutations in the glucokinase gene of the fetus result in reduced birth
weightAndrew T. Hattersley1, Frances Beards1, Elizabeth Ballantyne1, Maggie Appleton1, Rod Harvey2
& Sian Ellard11
Department of Vascular Medicine and Diabetes Research,
Postgraduate Medical School, University of Exeter, Barrack Road,
Exeter EX2 5AX, UK. 2
Dr Gray's Hospital, Elgin, Morayshire
IV30 1SN, Scotland, UK.
Correspondence should be addressed to Andrew T. Hattersley A.T.Hattersley@exeter.ac.ukLow birth weight and fetal thinness have been associated with non-insulin
dependent diabetes mellitus (NIDDM) and insulin resistance in childhood and
adulthood1,
2,
3,
4,
5,
6. It has been proposed that this association
results from fetal programming in response to the intrauterine environment7,
8. An alternative explanation is that the same genetic influences
alter both intrauterine growth and adult glucose tolerance. Fetal insulin
secretion in response to maternal glycaemia plays a key role in fetal growth,
and adult insulin secretion is a primary determinant of glucose tolerance.
We hypothesized that a defect in the sensing of glucose by the pancreas, caused
by a heterozygous mutation in the glucokinase gene9, could reduce
fetal growth and birth weight in addition to causing hyperglycaemia after
birth. In 58 offspring, where one parent has a glucokinase mutation, the inheritance
of a glucokinase mutation by the fetus resulted in a mean reduction of birth
weight of 533 g (P = 0.002). In 19 of 21 sibpairs discordant for the
presence of a glucokinase mutation, the child with the mutation had a lower
birth weight, with a mean difference of 521 g (P = 0.0002). Maternal
hyperglycaemia due to a glucokinase mutation resulted in a mean increase in
birth weight of 601 g (P = 0.001). The effects of maternal and fetal
glucokinase mutations on birth weight were additive. We propose that these
changes in birth weight reflect changes in fetal insulin secretion which are
influenced directly by the fetal genotype and indirectly, through maternal
hyperglycaemia, by the maternal genotype. This observation suggests that
variation in fetal growth could be used in the assessment of the role of genes
which modify either insulin secretion or insulin action.
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