Familial hyperproinsulinaemia due to a mutation substituting histidine for arginine at position 65 in proinsulin: identification of the mutation by restriction enzyme mapping.
Familial hyperproinsulinaemia is a rare genetic disorder characterized by point mutations in the insulin gene which impair the conversion of proinsulin to insulin. We report here three members of a two-generation Caucasian family in whom this syndrome was identified by unexplained hyperinsulinism associated with normal glucose tolerance and normal insulin sensitivity. Plasma insulin immunoreactivity showed a reduced affinity for the insulin receptor and eluted mainly, on Biogel chromatography, at the position of proinsulin. Analysis of the PCR-amplified insulin gene by restriction enzyme mapping revealed a new recognition site for the enzyme Nla III, indicating a Arg65 to His mutation. Sequence analysis of exon 3 confirmed this mutation in one allele of the gene.


CONCLUSIONS
This study reports a two-generation European-Caucasian family with hyperproinsulinaemia due to a substitution of His for Arg at position 65 in proinsulin, the seventh now identified worldwide and the second from Europe. The mutation generated a new restriction site on the insulin gene suggesting the usefulness of restriction enzyme mapping as a screening procedure.
Unité 30 INSERM, Hôpital Necker Enfants-Malades, Paris, France.
M
M
Collinet
M
M
Berthelon
P
P
Bénit
K
K
Laborde
B
B
Desbuquois
A
A
Munnich
J J
JJ
Robert
D000328:Adult; D001120:Arginine / Q000235:genetics*; D002648:Child; D005260:Female; D006639:Histidine / Q000235:genetics*; D006801:Humans; D006946:Hyperinsulinism / Q000235:genetics*; D007328:Insulin / Q000235:genetics*; D008297:Male; D017354:Point Mutation; D016133:Polymerase Chain Reaction; D011384:Proinsulin / Q000097:blood*; D015183:Restriction Mapping
D007328:Insulin; D006639:Histidine; D011384:Proinsulin; D001120:Arginine