Molecular Genetics of Joubert Syndrome

Abstract

Joubert syndrome (JS) is an autosomal recessive or X‐linked congenital cerebellar ataxia characterised by a peculiar hindbrain–midbrain malformation, the ‘molar tooth sign’ (MTS). JS is characterised by neonatal hypotonia which later evolves into ataxia, developmental delay, abnormal eye movements, breathing abnormalities and intellectual disability. This neurological presentation can be variably complicated by the involvement of multiple organs such as the kidneys, retina, liver and skeleton.

JS is genetically heterogeneous, with 26 causative genes identified to date. All genes encode for proteins of the primary cilium, a nearly ubiquitous subcellular organelle that plays essential roles in embryonic development and cell functioning. Indeed, JS is part of ciliopathies, an expanding group of disorders that share many clinical and genetic determinants. The marked clinical and genetic heterogeneity of JS and ciliopathies may be explained by oligogenic inheritance and the existence of genetic modifiers.

Key Concepts:

  • Joubert syndrome (JS) is a congenital ataxia with autosomal or X‐linked recessive inheritance.

  • The diagnostic hallmark of JS is a peculiar cerebellar and brainstem malformation, the so‐called ‘molar tooth sign’ recognisable on brain imaging.

  • Neurological features of JS include hypotonia, ataxia, developmental delay, intellectual impairment, oculomotor abnormalities and alterations of the breathing pattern in neonatal age.

  • JS may present with variable involvement of the eyes, kidneys, liver, polydactyly and oral‐facial defects.

  • JS is genetically heterogeneous, with 26 genes identified to date, that are overall responsible of about half cases.

  • JS pathogenesis is related to the dysfunction of the primary cilium, making JS part of the expanding group of ‘ciliopathies’.

  • The primary cilium is an immotile organelle, located of the surface of nearly every cell type, that plays key roles in cellular functioning and embryonic development.

  • Ciliopathies are characterised by wide clinical and genetic heterogeneity, and present significant clinical and genetic overlap among distinct conditions.

  • Such complexity has been partly explained by showing oligogenic inheritance and the existence of genetic modifiers of the phenotype.

Keywords: Joubert syndrome; Meckel syndrome; primary cilium; cerebellum; cerebellar hypoplasia; ciliopathies; cerebellar ataxia; molar tooth sign; oligogenic inheritance

Figure 1.

T1‐weighted brain magnetic resonance imaging of a patient with Joubert syndrome showing the typical ‘molar tooth sign’ (MTS). (a) Axial section at the pontomesencephalic junction showing a deepened interpeduncolar fossa (thick arrow), elongated and thickened superior cerebellar peduncles (thin arrows) and umbrella shaped fourth ventricle (arrowhead). (b) Parasagittal section showing thickened, elongated and horizontalized superior cerebellar peduncle (arrow) and cerebellar vermian hypodysplasia (arrowhead).

Figure 2.

Schematic representation of a primary cilium, that is anchored to the cell through the basal body. The transition zone, where most of JS‐related proteins cluster in the ‘Tectonic’ complex, represents a functional gate to regulate the flux of proteins in and out of the cilium, so that to maintain it as a highly compartmentalized structure. Proteins entering the primary cilium are then trafficked up and down the ciliary length by means of anterograde and retrograde intraflagellary transport (red and green arrows, respectively), that is mediated by specific proteins complexes. Two major developmental pathways (Shh and Wnt) require a functional cilium for their correct functioning.

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Mancini, Francesca, Romani, Marta, Micalizzi, Alessia, and Valente, Enza Maria(Oct 2014) Molecular Genetics of Joubert Syndrome. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0024288]