Genetic subtyping of XXXX by comprehensive mutation screening.

@entity1 @entity24363 @entity24749 @entity5 @entity2674 @entity53262 @entity47937 @entity56 @entity74 @entity2864 @entity7366 @entity2131 @entity11807
@entity11807 ( @entity11807 ) is a @entity74 with predisposition to @entity2131 and @entity5 . @entity56 to cross-linking agents is a cellular feature used to confirm the diagnosis. The mode of inheritance is autosomal recessive (12 subtypes) as well as X-linked (one subtype). Most genetic subtypes have initially been defined as "complementation groups" by cell fusion studies. Here we report a comprehensive genetic subtyping approach for @entity11807 that is primarily based on mutation screening, supplemented by protein expression analysis and by functional assays to test for pathogenicity of unclassified variants. Of 80 @entity11807 cases analyzed, 73 (91%) were successfully subtyped. In total, 92 distinct mutations were detected, of which 56 were novel (40 in @entity2864 , eight in @entity7366 , two in @entity2674 , three in @entity53262 , one in @entity47937 , and three in @entity24363 ). All known complementation groups were represented, except D2, J, L, and M. Three @entity1 could not be classified because proliferating cell cultures from the probands were lacking. In cell lines from the remaining four @entity1 , immunoblotting was used to determine their capacity to monoubiquitinate @entity24749 . In one case @entity24749 monoubiquitination was normal, indicating a defect downstream. In the remaining three cases monoubiquitination was not detectable, indicating a defect upstream. In the latter four @entity1 , pathogenic mutations in a known @entity11807 gene may have been missed, or these @entity1 might represent novel genetic subtypes. We conclude that direct mutation screening allows a molecular diagnosis of @entity11807 in the vast majority of @entity1 , even in cases where growing cells from affected individuals are unavailable. Proliferating cell lines are required in a minority (<15%) of the @entity1 , to allow testing for @entity24749 ubiquitination status and sequencing of @entity24749 using cDNA, to avoid interference from pseudogenes.
