Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity

Hong Chen, Satya Jawahar, Yimei Qian, Quyen Duong, Gayun Chan, Alex Parker, Joanne M. Meyer, Karen J. Moore, Susan Chayen, David J. Gross, Benjamin Glaser, M. Alan Permutt, Lloyd D. Fricker

Research output: Contribution to journalArticle

62 Citations (Scopus)

Abstract

Carboxypeptidase E (CPE) is involved in the biosynthesis of peptide hormones and neurotransmitters, including insulin. One of the features of type 2 diabetes mellitus (T2DM) is an elevation in the proinsulin level and/or proinsulin/insulin molar ratio, suggesting that mutations in proinsulin processing enzymes may contribute to the development of T2DM. We scanned CPE for mutations in a collection of Ashkenazi T2DM families and identified five novel single nucleotide polymorphisms (SNPs). An SNP in the 283rd codon, c.847C>T, changes arginine to tryptophan (R283W). The residue Arg283 is conserved among CPE orthologs as well as most enzymatically active metallocarboxypeptidases. Of the 272 Ashkenazi T2DM pedigrees screened, we found four families segregating R283W. Within these four families, patients who inherited one copy of this variant had much earlier age of onset for T2DM. The R283W CPE protein cleaves peptide substrates with substantially lower efficiencies and is less stable at elevated temperature. In addition, the R283W CPE variant has a narrower pH optimum and is much less active at pH 6.0-6.5, indicating that the R283W CPE variant would be substantially less active than wild type CPE in the trans-Golgi network and immature secretory vesicles where the enzyme functions in vivo. To summarize, we uncovered a rare non-conservative missense mutation in CPE and demonstrated that the mutant protein has altered enzymatic properties. We predict that this mutant could cause hyperproinsulinism and diabetes in the homozygous state.

Original languageEnglish (US)
Pages (from-to)120-131
Number of pages12
JournalHuman Mutation
Volume18
Issue number2
DOIs
StatePublished - 2001

Fingerprint

Carboxypeptidase H
Type 2 Diabetes Mellitus
Proinsulin
Genes
Single Nucleotide Polymorphism
Insulin
trans-Golgi Network
Mutation
Peptide Hormones
Secretory Vesicles
Missense Mutation
Mutant Proteins
Enzymes
Pedigree
Age of Onset
Codon
Tryptophan
Neurotransmitter Agents
Arginine

Keywords

  • Ashkenazi
  • Carboxypeptidase E
  • CPE
  • Metallocarboxypeptidase
  • MODY
  • NIDDM
  • SNP
  • T2DM
  • Type 2 diabetes mellitus

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. / Chen, Hong; Jawahar, Satya; Qian, Yimei; Duong, Quyen; Chan, Gayun; Parker, Alex; Meyer, Joanne M.; Moore, Karen J.; Chayen, Susan; Gross, David J.; Glaser, Benjamin; Permutt, M. Alan; Fricker, Lloyd D.

In: Human Mutation, Vol. 18, No. 2, 2001, p. 120-131.

Research output: Contribution to journalArticle

Chen, H, Jawahar, S, Qian, Y, Duong, Q, Chan, G, Parker, A, Meyer, JM, Moore, KJ, Chayen, S, Gross, DJ, Glaser, B, Permutt, MA & Fricker, LD 2001, 'Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity', Human Mutation, vol. 18, no. 2, pp. 120-131. https://doi.org/10.1002/humu.1161
Chen, Hong ; Jawahar, Satya ; Qian, Yimei ; Duong, Quyen ; Chan, Gayun ; Parker, Alex ; Meyer, Joanne M. ; Moore, Karen J. ; Chayen, Susan ; Gross, David J. ; Glaser, Benjamin ; Permutt, M. Alan ; Fricker, Lloyd D. / Missense polymorphism in the human carboxypeptidase E gene alters enzymatic activity. In: Human Mutation. 2001 ; Vol. 18, No. 2. pp. 120-131.
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AU - Jawahar, Satya

AU - Qian, Yimei

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AU - Chan, Gayun

AU - Parker, Alex

AU - Meyer, Joanne M.

AU - Moore, Karen J.

AU - Chayen, Susan

AU - Gross, David J.

AU - Glaser, Benjamin

AU - Permutt, M. Alan

AU - Fricker, Lloyd D.

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