Disease relevance of MEP1A

• MEP1A was previously mapped to human chromosome 6p, by the use of radiation and somatic cell hybrids, in the region containing the gene for autosomal recessive polycystic kidney disease (ARPKD) [1].
• 5. This PABA-peptide hydrolase thus represents a distinct intestinal enzyme, possibly bound to the brush-border membrane, which could account for the residual urinary PABA recovery observed in patients and animal models with exocrine pancreatic insufficiency [2].

High impact information on MEP1A

• In contrast, rat renal microvilli readily degraded h-TGF alpha, as did endopeptidase-2, which is located in rat renal and intestinal brush borders, but is absent from pig kidneys [3].
• Endopeptidase-2, the second endopeptidase in rat kidney brush border [Kenny & Ingram (1987) Biochem. J. 245, 515-524] has been further characterized in regard to its specificity and its contribution to the hydrolysis of peptides by microvillar membrane preparations [4].
• The metabolism of neuropeptides. Hydrolysis of peptides by the phosphoramidon-insensitive rat kidney enzyme 'endopeptidase-2' and by rat microvillar membranes [4].
• Only for the first named was endopeptidase-2 the dominant enzyme; for bradykinin it made an equal, and for substance P a minor, contribution [4].
• We now report the localization of MEP1A and MEP1B in the human genome [5].

Biological context of MEP1A

• The structural genes, MEP1A and MEP1B, for the alpha and beta subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively [5].
• MEP1A mapped to the short arm of chromosome 6 by the use of radiation and somatic cell hybrids [5].
• In two of these genes, MEP1A and RHAG, we identified two novel polymorphisms associated with the disease haplotype [6].
• Tissue specificity of the MEP1A gene expression was examined by dot blot analysis of poly(A) RNA from 50 different human tissues [7].
• We now report the fine mapping of MEP1A using yeast artificial chromosome clones, and linkage analysis of ARPKD families [1].

Anatomical context of MEP1A

• The MEP1A mRNA was detected for the first time in kidney and appendix in addition to colon and small intestine previously known to express the gene [7].
• Expression of a chimeric meprin-PPH alpha cDNA in COS-1 cells led to the synthesis of immature, transport-incompetent homodimers [8].
• PABA peptide hydrolase (PPH) from human enterocytes is comprised of two subunits, alpha and beta [8].

Other interactions of MEP1A

• The results from both physical and genetic mapping exclude MEP1A as a candidate for ARPKD [1].
• This mutant, but not the secretory form, coimmunoprecipitated with calnexin, indicating an involvement of this molecular chaperone in retaining PPH alpha in the ER [9].

Analytical, diagnostic and therapeutic context of MEP1A

• Fluorescence in situ hybridization (FISH) mapped both PACs (1e12, 65a14) to chromosome 6p21, confirming the MEP1A location [10].
• Southern blot analysis showed that sequences of PAC 65a14 and MEP1A were similar in the 3' end but different in the 5' end, revealing for the first time that the human genome may encode multiple interaction domains highly similar to those of the meprin alpha subunit [10].
• The deduced amino acid sequence showed 87% identity with that of meprin A, a mouse metallo-endopeptidase, sharing common properties with the rat enzyme, and 85% identity with the human intestinal enzyme, 'PABA-peptide hydrolase'. Northern blot analysis revealed the alpha-subunit to be encoded by a single mRNA species of 3.2-kb [11].

References