Cranio-Lenticulo-Sutural Dysplasia - a recently described genetic syndrome with late-closing fontanels

We delineated Cranio-lenticulo-sutural dysplasia (CLSD; Boyadjiev-Jabs syndrome, OMIM 607812) as a new autosomal-recessive genetic syndrome in a consanguineous family where five males and one female have similar craniofacial features (large and late-closing anterior fontanels, hypertelorism), early onset cataracts, and mild generalized skeletal dysplasia. Linkage analysis mapped the locus to chromosome 14q13-q21 and a F382L causative mutation was identified in SEC23A. Detailed molecular and biochemical analysis of wild type and mutant SEC23A, an integral member of the COPII-mediated ER-to-Golgi trafficking pathway, led to better characterization of intracellular trafficking in health and disease. A zebrafish morpholino model recapitulated the human phenotype and a Sec23a knockout mouse model is being developed. Recently, an unrelated Caucasion boy with clinical features consistent with CLSD was identified. Molecular analysis of SEC23A identified a novel heterozygous SEC23A mutation involving a highly conserved residue. This missense mutation was inherited from the unaffected father and was not present in 400 control chromosomes. No mutations were found in the maternal alleles and SEC23A real-time PCR analysis showed normal expression of the alleles. Biochemical characterization by in vitro ER budding assay is in progress in collaboration with Dr. Jinoh Kim, a cell biologist with special expertise in protein trafficking. Our data suggest that CLSD may be more common than previously thought and should be considered in the evaluation of patients with late-closing fontanels. Alternative inheritance patterns may exist for this syndrome.

Our current research is focused on identification and characterization of additional patients with CLSD and related defects of the COPII mediated protein trafficking.