Genetic basis of Joubert syndrome and related disorders of cerebellar development

Abstract

Over three decades have passed since Marie Joubert described the original proband for Joubert syndrome, a rare neurological disorder featuring absence of the cerebellar vermis (i.e. midline). Efforts at deciphering the molecular basis for this disease have been complicated by the clinical and genetic heterogeneity as well as extensive phenotypic overlap with other syndromes. However, progress has been made in recent years with the mapping of three genetic loci and the identification of mutations in two genes, AHI1 and NPHP1. These genes encode proteins with some shared functional domains, but their role in brain development is unclear. Clues may come from studies of related syndromes, including Bardet-Biedl syndrome and nephronophthisis, for which all of the encoded proteins localize to primary cilia. The data suggest a tantalizing connection between intraflagellar transport in cilia and brain development.