Pentalogy of Cantrell (POC) is a developmental disorder estimated to occur in 1-5.5 per 1 million live births with a 61% survival rate. The syndrome includes five features: 1) a defect in sternal fusion, often resulting in ectopia cordis, 2) a diaphragmatic hernia, allowing the abdominal organs to protrude into the thoracic cavity, 3) a weakened abdominal wall, often resulting in an omphalocele, 4) a missing or defective pericardium, and 5) structural and valvular defects in the heart, including ventricular septal defect and displacement of the aorta outlet to the right ventricle. Our laboratory has generated mice with a single amino acid substitution (R709C) in the non-muscle myosin IIB heavy chain (encoded by the gene Myh10) which phenocopy the human POC. Generation of the mouse model prompted us to initiate a clinical study in humans in which we conduct whole exome sequencing of POC patients and their parents to determine a possible genetic etiology for POC. The 28 probands currently in our study range from 1 day to 31 years of age at time of enrollment and exhibit different subsets of the five characteristic features of the disorder. We filtered for rare variants in the exome data that segregated with POC in each family. To date, we have identified one rare single nucleotide variant in the teneurin-4 gene (TENM4), which appears to exhibit incomplete penetrance for POC. We are also currently investigating a number of rare de novo SNVs identified in POC patients born to unaffected parents. To interpret the results, we are performing network level analyses, which indicate a potential common role for the proteins identified involving ubiquitination and cell death. Additionally, we have observed decreased apoptosis at both the developing sternum and valve cushions in our mouse model, supporting a role for an apoptotic pathway in the pathogenicity of POC.
| Kruszka, Paul; Uwineza, Annette; Mutesa, Leon et al. (2015) Limb body wall complex, amniotic band sequence, or new syndrome caused by mutation in IQ Motif containing K (IQCK)? Mol Genet Genomic Med 3:424-32 |
| Ma, Xuefei; Adelstein, Robert S (2014) A point mutation in Myh10 causes major defects in heart development and body wall closure. Circ Cardiovasc Genet 7:257-65 |
| Ma, Xuefei; Adelstein, Robert S (2014) The role of vertebrate nonmuscle Myosin II in development and human disease. Bioarchitecture 4:88-102 |
| Kim, Jong Hyun; Wang, Aibing; Conti, Mary Anne et al. (2012) Nonmuscle myosin II is required for internalization of the epidermal growth factor receptor and modulation of downstream signaling. J Biol Chem 287:27345-58 |
| Kim, Jong Hyun; Adelstein, Robert S (2011) LPA(1) -induced migration requires nonmuscle myosin II light chain phosphorylation in breast cancer cells. J Cell Physiol 226:2881-93 |
