Mutational Screening of CDO using dHPLC in Holoprosencephaly (HPE) Patients.

SABINA DOMENE; MAIA OUSPENSKAIA; ERICH ROESSLER; ROBERT KRAUSS; MAXIMILIAN MUENKE

New Orleans, Luisiana, USA

Congreso; American Society of Human Genetics (ASHG) Meeting; 2006

American Society of Human Genetics (ASHG)

Holoprosencepaly (HPE) is the most common structural anomaly of human braindevelopment, with a prevalence of 1 in 250 conceptuses and 1 in 16000 at birth.Mutations in at least eight different genes account for only 25 percent of the total cases.Among these HPE genes, several encode components of the Sonic Hedgehog (SHH)pathway: the secreted ligand SHH, its receptor, PTCH, and the transcription factorsGLI2 and ZIC2.CDO is the founding member of a distinct subfamily of the Ig superfamily (IgSF) thathas recently been described to bind Shh, and likely modulate its action in the forebrainduring early embriogenesis. Patterning of the midline of the ventral floorplate andmidface is particularly sensitive to Shh signaling strength; this might explain why Shhdepends on Cdo for augmentation of this important midline signal. In addition, theoriginally described Cdo knock-out mouse exhibits the hallmark facial defects associatedwith microforms of HPE, a single central incisor, which led to our study of thisgene as a potential candidate gene for HPE. Cdo is not essential for Shh signaling ingeneral, as other Shh-dependent body structures, such as the limb, develop normallyin Cdo-/- animals. DHPLC analysis for all 19 coding regions and intron-exon boundariesof human CDO (followed by sequencing of abnormal chromatograms) in 285 HPEpatients and 96 normal controls was performed. A total of 38 polymorphisms (detectedequally in patients and controls) and 6 missense mutations (that appear to be diseasespecific)were identified. It will be interesting to study the functional consequences ofthese missense mutations to see if they might underlie some cases of HPE alone, orin combination with other genes involved in midline development.