A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein

Garry R Cutting, Laura M. Kasch, Beryl J Rosenstein, Julian Zielenski, Lap Chee Tsui, Stylianos E. Antonarakis, Haig Kazazian

Research output: Contribution to journalArticle

Abstract

The gene responsible for cystic fibrosis (CF) has recently been identified and is predicted to encode a protein of 1,480 amino acids called the CF transmembrane conductance regulator (CFTR)1,2. Several functional regions are thought to exist in the CFTR protein, including two areas for ATP-binding, termed nucleotide-binding folds (NBFs), a regulatory (R) region that has many possible sites for phosphorylation by protein kinases A and C, and two hydrophobic regions that probably interact with cell membranes2. The most common CF gene mutation leads to omission of phenylalanine residue 508 in the putative first NBF, indicating that this region is functionally important2-4. To determine whether other mutations occur in the NBFs of CFTR, we determined the nucleotide sequences of exons 9, 10, 11 and 12 (encoding the first NBF) and exons 20, 21 and 22 (encoding most of the second NBF) from 20 Caucasian and 18 American-black CF patients. One cluster of four mutations was discovered in a 30-base-pair region of exon 11. Three of these mutations cause amino-acid substitutions at residues that are highly conserved among the CFTR protein, the multiple-drug-resistance proteins and ATP-binding membrane-associated transport proteins. The fourth mutation creates a premature termination signal. These mutations reveal a functionally important region in the CFTR protein and provide further evidence that CFTR is a member of the family of ATP-dependent transport proteins2,5.

Original languageEnglish (US)
Pages (from-to)366-369
Number of pages4
JournalNature
Volume346
Issue number6282
StatePublished - Jul 26 1990

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Cystic Fibrosis
Nucleotides
Mutation
Exons
Proteins
Adenosine Triphosphate
Cystic Fibrosis Transmembrane Conductance Regulator
Membrane Transport Proteins
Nucleic Acid Regulatory Sequences
Multiple Drug Resistance
Amino Acid Substitution
Cyclic AMP-Dependent Protein Kinases
Phenylalanine
Protein Binding
Base Pairing
Protein Kinase C
Genes
Carrier Proteins
Membrane Proteins
Phosphorylation

ASJC Scopus subject areas

  • General

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A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. / Cutting, Garry R; Kasch, Laura M.; Rosenstein, Beryl J; Zielenski, Julian; Tsui, Lap Chee; Antonarakis, Stylianos E.; Kazazian, Haig.

In: Nature, Vol. 346, No. 6282, 26.07.1990, p. 366-369.

Research output: Contribution to journalArticle

Cutting, Garry R ; Kasch, Laura M. ; Rosenstein, Beryl J ; Zielenski, Julian ; Tsui, Lap Chee ; Antonarakis, Stylianos E. ; Kazazian, Haig. / A cluster of cystic fibrosis mutations in the first nucleotide-binding fold of the cystic fibrosis conductance regulator protein. In: Nature. 1990 ; Vol. 346, No. 6282. pp. 366-369.
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