CHARACTERIZATION OF THE HUMAN MUCIN GENE MUC5AC - A CONSENSUS CYSTEINE-RICH DOMAIN FOR 11P15 MUCIN GENES

To date five human mucin cDNAs (MUC2, 5A, 5B, 5C and 6) mapped to 11p1 5.3-15.5, so it appears that this chromosome region might contain seve ral distinct gene loci for mucins. Three of these cDNAs, MUC5A, B and C, were cloned in our laboratory and previously published. A common nu mber, 5, was recommended by the Human Gene Mapping Nomenclature Commit tee to designate them because of their common provenance from human tr acheobronchial mucosa. In order to define whether they are products of the same gene locus or distinct loci, we describe in this paper physi cal mapping of these cDNAs using the strategy of analysis of CpG islan ds by pulse-held gel electrophoresis. The data suggest that MUC5A and MUC5C are part of the same gene (called MUC5AC) which is distinct from MUC5B. In the second part of this work, complete sequences of the ins erts corresponding to previously described (JER47, JER58) and novel (J ER62, JUL32, MAR2, MAR10 and MAR11) cDNAs of the so-called MUC5AC gene are presented and analysed. The data show that in this mucin gene, th e tandem repeat domain is interrupted several times with a subdomain e ncoding a 130 amino acid cysteine-rich peptide in which the TR3A and T R3B peptides previously isolated by Rose et al. [Rose, Kaufman and Mar tin (1989) J. Biol. Chem., 264, 8193-8199] from airway mucins are foun d. A consensus peptide sequence for these subdomains involving invaria nt positions of most of the cysteines is proposed. The consensus nucle otide sequence of this subdomain is also found in the MUC2 gene and in the MUC5B gene, two other mucin genes mapped to 11p15. The functional significance for secreted mucins of these cysteine-rich subdomains an d the modular organization of mucin peptides are discussed.