IMPLICATIONS OF INTRAGENIC MARKER HOMOZYGOSITY AND HAPLOTYPE SHARING IN A RARE AUTOSOMAL RECESSIVE DISORDER - THE EXAMPLE OF THE COLLAGEN TYPE-XVII (COL17A1) LOCUS IN GENERALIZED ATROPHIC BENIGN EPIDERMOLYSIS-BULLOSA

Generalised atrophic benign epidermolysis bullosa (GABEB) is a form of junctional epidermolysis bullosa with a recessive mode of inheritance , The gene considered likely to be involved in this disease is COL17A1 , since in the majority of GABEB patients the product of that gene, th e 180-kD bullous pemphigoid antigen (BP180), is undetectable in skin. We have identified an intragenic COL17A1 microsatellite marker for whi ch 83% of randomly selected control individuals are heterozygous. We o bserved homozygosity for different alleles of this marker in five out of six collagen type XVII-negative GABEB patients of different Europea n descent. Five of the six COL17A1 alleles of three patients originati ng from the eastern part of The Netherlands were identical, as were th e haplotypes including flanking markers. The 2342delG mutation was ide ntified in all these five alleles, This confirms the expectation that due to genetic drift and hidden inbreeding for an autosomal recessive disorder with low gene frequency, such as collagen type XVII-negative GABEB. most disease alleles from a restricted geographical area will b e ''identical by descent''. Our results demonstrate that involvement o f a candidate gene can be confirmed by looking for identity by descent of highly informative intragenic markers.