Stephen P. Bryant

Plectin deficiency results in muscular dystrophy with epidermolysis bullosa.

We report that mutation in the gene for plectin, a cytoskeleton–membrane anchorage protein, is a cause of autosomal recessive muscular dystrophy associated with skin blistering (epidermolysis bullosa simplex). The evidence comes from absence of plectin by antibody staining in affected individuals from four families, supportive genetic analysis (localization of the human plectin gene to chromosome 8q24.13–qter and evidence for disease segregation with markers in this region) and finally the identification of a homozygous frameshift mutation detected in plectin cDNA. Absence of the large multifunctional cytoskeleton protein plectin can simultaneously account for structural failure in both muscle and skin.

The Integrated Genomic Database (IGD)s

Mapping genes using human pedigrees involves analysing the co-segregation of polymorphic markers with a trait phenotype. This technique exploits the pattern of meiotic recombination in the family to deduce the likely location of the unknown gene. In some cases, it is possible to visualize the transmission of haplotypes within a family and identify flanking loci, but more usually, genetic locations are estimated with statistical methods. Although genetic analysis in this way is supported by a variety of efficient and novel algorithms, implemented in a variety of programs, the rate limiting step continues to be the integration of data and software tools. The Integrated Genomic Database (IGD) approach offers an opportunity to remove the bottleneck and enhance the productivity of the linkage analyst. In this paper, we describe an approch to this problem using the IGD methods. We demonstrate the feasibility of IGD to increase the productivity of gene mapping projects and to facilitate communication between the clinic and the laboratory.

Isolation and mapping of three new polymorphic markers to chromosomes 3, 20 and 21

Screening of single human chromosome plasmid libraries using a digoxygenin labelled (AAAT)15 oligonucleotide probe led to the identification of several positive clones. DNA sequence analysis of these was carried out and showed the presence of a number of simple DNA repeats. Oligonucleotide primers were designed from the sequences flanking these repeats and tested in PCR amplification reactions of human genomic DNA. Three of the markers tested were shown to be polymorphic with heterozygosities ranging from 40% to 69%. The markers were assigned to chromosomes using a panel of monochromosomal somatic cell hybrids combined with linkage analysis using DNA from the CEPH panel of families. The markers designated (AAAT)11, (AAAT)12 and (CA)19 were thus assigned to chromosomes 3, 21 and 20 respectively.