Langlois_1988_Am.J.Hum.Genet_43_A191

The basic defect causing human LPL deficiency has been studied using a human LPL cDNA clone (HLPL26). Genomic DNA of 15 probands from 11 families with this inherited disorder was analysed by southern blot hybridization and compared to 300 controls. One proband was found to have two abnormal restriction fragments when the DNA was digested with 13 different enzymes. Restriction mapping using subclones of HLPL26 revealed that the mutant allele inherited from his mother is the result of a 6kb deletion and the mutant allele inherited from the father the result of a 2kb insertion. Six probands from 3 different families were found to have an insertion similar to that found in the initial proband based on detailed restriction mapping with 8 different enzymes. The ancestral backgrounds of these 4 families are different representing Irish, English, French, German and Polish descent for many generations. The question whether this insertional event can be explained by a single origin occuring in the distant past or whether it relates to multicentric origins has been studied by analysis of RFLP within the LPL gene. In 2 of the 4 families, the haplotypes are similar and suggest a single origin for this mutation In the other two families the insertional haplotype is likely to be similar but this could not be proven due to absence of DNA from a crucial family relative. Detailed restriction map- ping of the insertion revealed that it was unlikely to be a duplication of neighbouring DNA and that it was not similar to the restriction map of the consensus sequence of human LI elements. This suggests there are other novel mechanisms of insertional mutagenesis in human genetic disease besides transpostion of mobile LI repetitive elements. Major insertional events are rare causes of mutagenesis in the human genome. Our results demonstrate that LPL deficiency is an autosomal recessive disorder for which major rearrangements account for approximately 25% of the mutations. Within this gene a single common insertion has been identified