Permanent neonatal diabetes caused by glucokinase deficiency: inborn error of the glucose-insulin signaling pathway.
Neonatal diabetes can be either permanent or transient. We have recently shown that permanent neonatal diabetes can result from complete deficiency of glucokinase activity. Here we report three new cases of glucokinase-related permanent neonatal diabetes. The probands had intrauterine growth retardation (birth weight <1,900 g) and insulin-treated diabetes from birth (diagnosis within the first week of life). One of the subjects was homozygous for the missense mutation Ala378Val (A378V), which is an inactivating mutation with an activity index of only 0.2% of wild-type glucokinase activity. The second subject was homozygous for a mutation in the splice donor site of exon 8 (intervening sequence 8 [IVS8] + 2T-->G), which is predicted to lead to the synthesis of an inactive protein. The third subject (second cousin of subject 2) was a compound heterozygote with one allele having the splice-site mutation IVS8 + 2T-->G and the other the missense mutation Gly264Ser (G264S), a mutation with an activity index of 86% of normal activity. The five subjects with permanent neonatal diabetes due to glucokinase deficiency identified to date are characterized by intrauterine growth retardation, permanent insulin-requiring diabetes from the first day of life, and hyperglycemia in both parents. Autosomal recessive inheritance and enzyme deficiency are features typical for an inborn error of metabolism, which occurred in the glucose-insulin signaling pathway in these subjects.
Njølstad
Pål R
PR
Department of Pediatrics, Haukeland University Hospital, University of Bergen, Norway. pal.njolstad@uib.no
Sagen
Jørn V
JV
Bjørkhaug
Lise
L
Odili
Stella
S
Shehadeh
Naim
N
Bakry
Doua
D
Sarici
S Umit
SU
Alpay
Faruk
F
Molnes
Janne
J
Molven
Anders
A
Søvik
Oddmund
O
Matschinsky
Franz M
FM
D001483:Base Sequence; D002239:Carbohydrate Metabolism, Inborn Errors / Q000201:enzymology* / Q000235:genetics; D017931:DNA Primers; D003920:Diabetes Mellitus / Q000151:congenital* / Q000235:genetics*; D005091:Exons; D005260:Female; D005819:Genetic Markers; D005941:Glucokinase / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics* / Q000378:metabolism; D005947:Glucose / Q000502:physiology; D006801:Humans; D007231:Infant, Newborn; D007328:Insulin / Q000502:physiology*; D007438:Introns; D007700:Kinetics; D008297:Male; D008958:Models, Molecular; D009154:Mutation; D010375:Pedigree; D016133:Polymerase Chain Reaction; D011401:Promoter Regions, Genetic; D011487:Protein Conformation; D015398:Signal Transduction / Q000235:genetics; D044465:White People
D017931:DNA Primers; D005819:Genetic Markers; D007328:Insulin; D005941:Glucokinase; D005947:Glucose