A somatic MAP3K3 mutation is associated with verrucous venous malformation.
Verrucous venous malformation (VVM), also called "verrucous hemangioma," is a non-hereditary, congenital, vascular anomaly comprised of aberrant clusters of malformed dermal venule-like channels underlying hyperkeratotic skin. We tested the hypothesis that VVM lesions arise as a consequence of a somatic mutation. We performed whole-exome sequencing (WES) on VVM tissue from six unrelated individuals and looked for somatic mutations affecting the same gene in specimens from multiple persons. We observed mosaicism for a missense mutation (NM_002401.3, c.1323C>G; NP_002392, p.Iso441Met) in mitogen-activated protein kinase kinase kinase 3 (MAP3K3) in three of six individuals. We confirmed the presence of this mutation via droplet digital PCR (ddPCR) in the three subjects and found the mutation in three additional specimens from another four participants. Mutant allele frequencies ranged from 6% to 19% in affected tissue. We did not observe this mutant allele in unaffected tissue or in affected tissue from individuals with other types of vascular anomalies. Studies using global and conditional Map3k3 knockout mice have previously implicated MAP3K3 in vascular development. MAP3K3 dysfunction probably causes VVM in humans.
Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Javier A
JA
Couto
Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Matthew P
MP
Vivero
Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Pathology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
Harry P W
HP
Kozakewich
Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA.
Amir H
AH
Taghinia
Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA.
John B
JB
Mulliken
Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA; Department of Orthopaedic Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Department of Genetics, Harvard Medical School, Boston, MA 02115, USA; Howard Hughes Medical Institute, Boston Children's Hospital, Boston, MA 02115, USA.
Matthew L
ML
Warman
Department of Plastic and Oral Surgery, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA; Vascular Anomalies Center, Boston Children's Hospital, Boston, MA 02115, USA. Electronic address: arin.greene@childrens.harvard.edu.
Arin K
AK
Greene
D000293:Adolescent; D000483:Alleles; D002648:Child; D002675:Child, Preschool; D005260:Female; D006801:Humans; D007223:Infant; D007642:Keratosis / Q000235:genetics; D048748:MAP Kinase Kinase Kinase 3 / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020125:Mutation, Missense; D012878:Skin Neoplasms / Q000235:genetics*; D055815:Young Adult
D048748:MAP Kinase Kinase Kinase 3; C482625:MAP3K3 protein, human