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Posttranslational cleavage of proinsulin is blocked by a point mutation in familial hyperproinsulinemia.
Familial hyperproinsulinemia is characterized by the accumulation of proinsulin-like material (PLM) in the plasma of affected patients. This disorder is inherited in an autosomal dominant fashion. The accumulation of PLM is thought to be due to the impaired conversion of proinsulin to insulin. Although PLM has been suggested to have an amino acid substitution, it has been impossible to locate and identify a substituted amino acid, due to the difficulty in isolating sufficient amounts of PLM from plasma samples. Therefore, we analyzed leukocyte DNA from one member of a proinsulinemic family, and we found a point mutation that changed guanine to adenine in the insulin gene. This transition implies that a substitution of histidine for arginine has occurred at amino acid position 65. Furthermore, it indicates that arginine at 65 is essential for the conversion of proinsulin to insulin. Our results suggest a novel mechanism by which disease can be incurred: a heritable disorder can result from a posttranslational processing abnormality caused by a point mutation.
PMID: 4019786 [PubMed - indexed for MEDLINE]
PMCID: PMC423787
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Cited by 10 PubMed Central articles
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A mutation in the B chain coding region is associated with impaired proinsulin conversion in a family with hyperproinsulinemia.
Chan SJ, Seino S, Gruppuso PA, Schwartz R, Steiner DF.
Proc Natl Acad Sci U S A. 1987 Apr; 84(8):2194-7.
[Proc Natl Acad Sci U S A. 1987]
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Molecular basis of hemophilia B: a defective enzyme due to an unprocessed propeptide is caused by a point mutation in the factor IX precursor.
Diuguid DL, Rabiet MJ, Furie BC, Liebman HA, Furie B.
Proc Natl Acad Sci U S A. 1986 Aug; 83(16):5803-7.
[Proc Natl Acad Sci U S A. 1986]
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A superactive insulin: [B10-aspartic acid]insulin(human).
Schwartz GP, Burke GT, Katsoyannis PG.
Proc Natl Acad Sci U S A. 1987 Sep; 84(18):6408-11.
[Proc Natl Acad Sci U S A. 1987]
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