Response to Letter by Stahl and Felbor
We would like to thank the authors Sonja Stahl and Ute Felbor for their very helpful comments on our article entitled “Cerebral Venous Malformations Have Distinct Genetic Origin from Cerebral Cavernous Malformations.” In this article, we presented a rare family in which 2 family members, the father and daughter, had documented cerebral cavernous malformations (CCM), and another daughter had documented cerebral venous malformations (CVM). We had hypothesized that both types of lesions may be attributed to the same genetic defect, and proceeded to sequence all 3 genes known to cause CCM: KRIT1, Malcavernin, and PDCD10. As a result of our sequencing analysis, we determined that the father and daughter both possessed a frameshift mutation in exon 19 of the KRIT1 gene, whereas the daughter with the CVM did not carry this mutation. We concluded that CCM and CVM were genetically distinct entities and used this data as further evidence to support the idea that CVMs are benign developmental anomalies that should not be treated clinically.
In their letter, Stahl and Felbor correctly point out that the string of 4 thymine residues (positions 2055 to 2058) is in fact the wild-type sequence and the published figure contains an error. In the original figure the family members affected with CCM were shown with the wild-type sequence and the individual with CVM was shown carrying the mutation. In fact the sequence traces were presented in reverse: the 2 family members with CCM should have been shown to carry the frame-shift mutation attributable to a T deletion, and the member with CVM should have been shown with the wild-type sequence. The corrected figure along with sequencing results of all family members, showing the frame shift mutation in the members affected with CCM, is now presented (Figure 1). As Stahl and Felbor also point out, the sequence traces presented in the original figure, and those presented here, have been TA cloned (Invitrogen), resulting in the presentation of the individual DNA strands clearly showing that the frame shift mutation is the result of a −T deletion. The original sequencing results that suggested the frame-shift mutation are now included (Figure 2). We have also replicated these results. We regret the confusion that our mislabeling of the original figure caused and trust that the new figure (Figure 1) resolves the central question raised by Stahl and Felbor.
In sum, the conclusions drawn in the published article, namely that CCM is attributable to a frameshift mutation in KRIT1, remain unchanged. These results strongly suggest that CCM is genetically distinct from CVM and that CVM, at least in this family, is not attributable to a mutation in the CCM1 gene, KRIT1.