Katherine Rojas

The structural genes, MEP1A and MEP1B, for the α and β subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively ☆

Meprins are cell membrane, oligomeric metalloendopeptidases composed of two distinct but evolutionarily related subunits, {alpha} and {beta}. The structural genes for the meprin subunits, Mep-1{alpha} and Mep-1{beta}, have been previously mapped to chromosomes 17 and 18, respectively, of the mouse genome. We now report the localization of MEP1A and MEP1B in the human genome. MEP1A mapped to the short arm of chromosome 6 by the use of radiation and somatic cell hybrids. More specifically, it is localized between the centromere and GSTA2 in 6p11-p12. MEP1B mapped to chromosome 18, by the use of somatic cell hybrids, in 18q12.2-q12.3, proximal to the TTR/PALB gene. As in the mouse genome, the two homologous human structural genes for {alpha} and {beta} (50% identical on the cDNA level) are unlinked. These new markers on human chromosomes 6 and 18 extend the region of known linkage homology with mouse chromosomes 17 and 18, respectively, and provide new molecular access to regions of the human genome. 18 refs., 2 figs.

Short communicationThe structural genes, MEP1A and MEP1B, for the α and β subunits of the metalloendopeptidase meprin map to human chromosomes 6p and 18q, respectively☆

Meprins are cell membrane, oligomeric metalloendopeptidases composed of two distinct but evolutionarily related subunits, {alpha} and {beta}. The structural genes for the meprin subunits, Mep-1{alpha} and Mep-1{beta}, have been previously mapped to chromosomes 17 and 18, respectively, of the mouse genome. We now report the localization of MEP1A and MEP1B in the human genome. MEP1A mapped to the short arm of chromosome 6 by the use of radiation and somatic cell hybrids. More specifically, it is localized between the centromere and GSTA2 in 6p11-p12. MEP1B mapped to chromosome 18, by the use of somatic cell hybrids, in 18q12.2-q12.3, proximal to the TTR/PALB gene. As in the mouse genome, the two homologous human structural genes for {alpha} and {beta} (50% identical on the cDNA level) are unlinked. These new markers on human chromosomes 6 and 18 extend the region of known linkage homology with mouse chromosomes 17 and 18, respectively, and provide new molecular access to regions of the human genome. 18 refs., 2 figs.

Somatic cell hybrid deletion map of human chromosome 18.

The creation of a physical map of chromosome 18 will be useful for the eventual identification of specific chromosomal regions that are critical in the occurrence of Edwards syndrome, the 18q- syndrome, and the 18p- syndrome. To begin the investigation of these syndromes, a physical map has been constructed to order random DNA fragments to specific portions of chromosome 18. A set of somatic cell hybrids that retain deletions or translocations involving chromosome 18 has been isolated and characterized. Over 200 lambda phage from a chromosome 18-specific library have been localized to 11 distinct regions of chromosome 18 using the chromosomal breakpoints present in the somatic cell hybrids.

Development of diagnostic tools for the analysis of 5p deletions using interphase FISH

Cri-du-chat syndrome is associated with a deletion of the short arm of chromosome 5. Through the phenotypic and molecular analyses of individuals with a subset of the features associated with the syndrome, the genes involved in the syndrome have been mapped to two distinct critical regions. Deletion of a critical region in 5p15.2 results in the distinct facial features associated with the syndrome as well as the severe mental and developmental delay, while a deletion of 5p15.3 is associated only with the characteristic cat-like cry, the key diagnostic feature of the syndrome. Therefore, subtle differences in the extent of the 5p deletion can have a profound affect on the prognosis of the patient. In order to more easily differentiate between deletions that lead to the cri-du-chat syndrome phenotype and deletions that lead only to the isolated cat-like cry, we have constructed YAC contigs that span both critical regions. The YAC clones have been used to isolate cosmids mapping to each critical region and cosmids that lie just within the two critical region boundaries have been identified. We report here on the use of these cosmids as probes for fluorescent in situ hybridization experiments on interphase nuclei as a means of more accurately differentiating between small 5p deletions that coincide with a complete cri-du-chat syndrome phenotype and the severe mental and developmental delay that is associated with it and deletions that only delete the distal critical region that coincide with the isolated cat-like cry and a much improved prognosis.

Integration of the 1993-94 genethon genetic linkage map for chromosome 18 with the physical map using a somatic cell hybrid mapping panel

There have been concerted efforts in the past 5 years to create a high-resolution genetic map for all of the human chromosomes that contain markers that can be analyzed using the polymerase chain reaction technique. In 1992, a second-generation genetic linkage map of the human genome was presented that was composed of such markers. Additional genetic linkage maps have also been described that are mostly composed of simple-tandem repeat markers. And recently, Gyapay et al. expanded their initial genetic map and described the generation of a higher resolution human genetic map that was composed of over 2000 genetic markers. Unfortunately, most published genetic maps contain minimal information about the physical location of the markers. Since the physical location of most diseases are described based on where they map relative to a G-banded chromosome, it would be of use to determine the physical location of all genetic markers. 9 refs., 1 fig.

Variability in a family with an insertion involving 5p

Cri-du-chat syndrome is due to a partial deletion of the short arm of chromosome 5 and comprises a catlike cry, minor facial anomalies, growth delays, and psychomotor retardation. We identified a family with an insertion involving chromosome areas 5p and 16q. Four relatives are balanced carriers and have a normal phenotype, 5 have inherited the insertion in an unbalanced form with 2 resulting in partial trisomy of 5p and 3 in partial monosomy of 5p. The 3 individuals show a variable phenotype with respect to mental delay and some of the findings of cri-du-chat syndrome. The extent of the 5p deletion in this family was determined using previously mapped markers. The deletion in this family was informative for further refining the phenotypic map for the cri-du-chat syndrome. This family demonstrates the importance of performing phenotype-genotype correlation studies based on the presence rather than the absence of abnormalities.

Identification and localization of microsatellite markers covering human chromosome 18

To generate microsatellite markers from chromosome 18, we have cytogenetically localized a large number of lambda phage using a deletion mapping panel of somatic cell hybrids. Here we describe the identification of 65 new CA-repeat-containing phage and the localization of five markers developed in other laboratories. This approach allows the selection of a subset of markers that are well spaced across the chromosome and can be developed as genetic markers. The use of PCR-based markers should allow for the rapid genomic screening of disease genes on chromosome 18.