Molecular genetics of Meckel-Gruber syndrome, and functional characterization of meckelin and MKS1

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Neural tube defects (NTDs) occur in 1 per 1,000 births, and cleft lip and palate occurs in 1 per 550 births. NTDs and clefting problems are the most common forms of birth defect. The most common syndromic form of NTD is Meckel-Gruber syndrome (MKS) which is an inherited condition with brain, liver and kidney defects that arise during embryonic development. In addition, cleft lip and palate is a common clinical feature of MKS. Recently, we found that MKS is caused by changes in a unique gene that makes a large, novel protein that we have called meckelin. Meckelin carries developmental signals from the outside to the inside of a cell, controlling how the cell will behave during embryonic development. This regulation is lost if meckelin is defective or absent. Meckelin is a component of primary cilia, which are finger-like projections from cells. Cilia are thought to detect and respond to chemical or mechanical cues, such as fluid flow, during the formation of the neural tube and other tubular structures. We aim to have a deeper understanding of the molecular roles of meckelin and other proteins found at cilia during embryonic development, and how these processes go wrong in human diseases. We hope that the work will also provide key insights into the causes of complex genetic diseases, including NTDs such as spina bifida, and cleft lip and palate.