Mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia
A family has recently been described in which hyperproinsulinemia is inherited in an autosomal dominant pattern, suggesting a structural abnormality in the proinsulin molecule as the basis for this disorder. However, unlike two previous kindreds with a similar syndrome, the serum proinsulin-like material in this family did not appear to be an intermediate conversion product but instead behaved like normal human proinsulin by several criteria. To further characterize this disorder the authors isolated and sequenced the insulin gene of the propositus. Leukocyte DNA was cloned in lambdagt-WES and recombinants containing the two insulin alleles, lambdaMD41 and lambdaMD51, were isolated by plaque hybridization. DNA sequencing of lambdaMD51 showed that it contained the normal coding sequence for human preproinsulin. Sequence analysis of lambdaMD41, however, revealed a single nucleotide substitution in the codon for residue 10 of proinsulin (CAC ..-->.. GAC) that predicts the exchange of aspartic acid for histidine in the insulin B chain region. This mutation was also found in an insulin allele cloned from a second affected family member (propositus's father). These results strongly implicate this mutation as the cause of the hyperproinsulinemia in this family. Inhibition of the conversion of proinsulin to insulin may be related to altered folding and/or self-association properties of the (Asp/sup 10/)proinsulin.
- Research Organization:
- Univ. of Chicago, IL (United States)
- OSTI ID:
- 6072017
- Journal Information:
- Proc. Natl. Acad. Sci. U.S.A.; (United States), Vol. 84:8
- Country of Publication:
- United States
- Language:
- English
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Related Subjects
GENES
DNA SEQUENCING
HEREDITARY DISEASES
PATHOGENESIS
INSULIN
METABOLISM
DNA-CLONING
DOMINANT MUTATIONS
MAN
METABOLIC DISEASES
PHOSPHORUS 32
ANIMALS
BETA DECAY RADIOISOTOPES
BETA-MINUS DECAY RADIOISOTOPES
CLONING
DAYS LIVING RADIOISOTOPES
DISEASES
HORMONES
ISOTOPES
LIGHT NUCLEI
MAMMALS
MUTATIONS
NUCLEI
ODD-ODD NUCLEI
PEPTIDE HORMONES
PHOSPHORUS ISOTOPES
PRIMATES
RADIOISOTOPES
STRUCTURAL CHEMICAL ANALYSIS
VERTEBRATES
550401* - Genetics- Tracer Techniques