Mutational patterns in <i>CBL</i>.

<p><b>A</b>: Sample 45 had a 6 bp tandem duplication in CBL leading to the insertion of the amino acids valine (V) and aspartic acid (D) after position 390. <b>B</b>: One sample identified in a cohort screen for mutations in <i>CBL</i> exons 8 and 9 carried two mutations, one in exon 8 (W408C) and a second one in intron 8 at the splice acceptor site (G to A). PCR subcloning and analysis of colony DNA revealed that the two mutations are on different alleles. Depicted are two representative colonies. Colony 43 has the mutation in exon 8 but not in intron 8 whereas colony 17 shows the opposite case. <b>A</b>, <b>B</b>: Depicted are the genomic (letters) as well as the respective amino acid (box chains) sequences. Numbers indicate amino acid positions in the Cbl protein. Amino acids, which are substituted due to mutations are in red boxes. The splice site alteration is a red circle. Black arrows indicate the positions of the mutations below the Sanger sequencing traces. <b>C</b>: Overview of <i>CBL</i> mutagenesis in MPN. Different genetic mechanisms are involved in increasing mutant gene dosage of <i>CBL</i>. Each panel shows schematically the two parental copies of chromosomes 11 (blue and yellow) and the <i>CBL</i> gene (white rectangles). Mutations are indicated with asterisks. From left to right: heterozygous mutation in <i>CBL</i>; uniparental disomy introduces homozygous <i>CBL</i> mutations; gain of a part of chromosome 11q leads to a duplication of the <i>CBL</i> mutation while one wild type allele is still present; compound heterozygosity established by two different mutations on the different alleles of the <i>CBL</i> gene in one cell. In addition, the loss of a part of chromosome 11q deleting one <i>CBL</i> allele and leaving the other allele unaffected (wild type <i>CBL</i>) is likely to introduce phenotypes due to haploinsufficiency.