The Joubert-Meckel-Nephronophthisis Spectrum of Ciliopathies

Abstract

The Joubert syndrome (JS), Meckel syndrome (MKS), and nephronophthisis (NPH) ciliopathy spectrum could be the poster child for advances and challenges in Mendelian human genetics over the past half century. Progress in understanding these conditions illustrates many core concepts of human genetics. The JS phenotype alone is caused by pathogenic variants in more than 40 genes; remarkably, all of the associated proteins function in and around the primary cilium. Primary cilia are near-ubiquitous, microtubule-based organelles that play crucial roles in development and homeostasis. Protruding from the cell, these cellular antennae sense diverse signals and mediate Hedgehog and other critical signaling pathways. Ciliary dysfunction causes many human conditions termed ciliopathies, which range from multiple congenital malformations to adult-onset single-organ failure. Research on the genetics of the JS-MKS-NPH spectrum has spurred extensive functional work exploring the broadly important role of primary cilia in health and disease. This functional work promises to illuminate the mechanisms underlying JS-MKS-NPH in humans, identify therapeutic targets across genetic causes, and generate future precision treatments.

Keywords: Joubert; Meckel; ciliopathies; genetics; nephronophthisis.

Figure 1

Diagnostic features of JS visualized by MRI. In each pair of images, the left is from an affected individual, and the right is from an unaffected individual of the same age. (a) MTS on a T2-weighted axial image due to the combination of long, thick superior cerebellar peduncles (the roots of the tooth) and a deep interpeduncular fossa (the cutting surface of the tooth). This appearance is not always captured in a single plane, so it is important to evaluate the MRI as a whole rather than relying on a single image. (b) Superior cerebellar foliar dysplasia (white bracket) on an axial T2-weighted image, which is sometimes seen in the absence of MTS in individuals carrying pathogenic variants in the JS-associated genes (note that the folia at this level are usually shaped like a U or V). (c) Horizontally oriented superior cerebellar peduncle (red arrowhead) on a T1-weighted parasagittal image. (d) Vermis hypoplasia (dotted outline), elevated roof of the fourth ventricle, and rostrally displaced fastigium on a T1-weighted sagittal image. (e) Long, thick superior cerebellar peduncles (red arrowhead) on a T2-weighted coronal image. (f) Cerebellar cleft (red arrow, indicating fluid at the cerebellar midline) on a T2-weighted coronal image. Abbreviations: JS, Joubert syndrome; MRI, magnetic resonance imaging; MTS, molar tooth sign. Figure adapted from Reference .

Figure 2

JS-MKS-NPH phenotypic and genetic overlap and gene discovery time line. (a) Coarse phenotypic spectrum, from severe MKS to milder JS. This schematic is based on overlapping genetic etiology and phenotypic manifestations. (b) Overlap of genetic etiology from the JS-MKS-NPH spectrum. Genes associated with JS are in blue, those associated with MKS are in purple, and those associated with isolated NPH are in red, with overlap as indicated by shading. (c) Time line of published JS-MKS-NPH-associated genes. Abbreviations: JS, Joubert syndrome; MKS, Meckel syndrome; MRI, magnetic resonance imaging; MTS, molar tooth sign; NPH, nephronophthisis.

Figure 3

Genetic causes in a large JS cohort, showing the proportion of individuals with JS who carry two rare deleterious variants in each gene. Each bar is broken down to illustrate the relative frequency of the observed variants in each gene: Green indicates two missense variants or small in-frame indels, blue indicates one truncating and one missense variant (including small in-frame indels), red indicates two truncating variants (including nonsense, frameshift, and canonical splice-site variants), and yellow indicates two larger deletions. For each bar, n indicates the total number of people with JS who have variants assessed in this graph. Abbreviations: indel, insertion or deletion; JS, Joubert syndrome. Figure adapted from Reference .

Figure 4

Proportions of individuals with JS, MKS, or isolated NPH who carry two rare deleterious variants in TMEM67. The colors on each bar illustrate the relative frequency of the variants in each diagnostic category: Green indicates two missense variants or small in-frame indels, blue indicates one truncating and one missense variant (including small in-frame indels), red indicates two truncating variants (including nonsense, frameshift and canonical splice-site variants), and yellow indicates two larger deletions. For each bar, n indicates the total number of people found in the literature with each diagnosis who have the variants assessed in this graph. Abbreviations: indel, insertion or deletion; JS, Joubert syndrome; MKS, Meckel syndrome; NPH, nephronophthisis.

Figure 5

JS-MKS-NPH protein localization and IFT. (a) JS-associated proteins grouped by their localization in steady-state cilia. The TZ is subdivided into the NPHP module (dark blue) and the MKS module (light blue). The ciliary membrane is continuous with the plasma membrane. (b) MKS-associated proteins grouped by their localization in steady-state cilia. (c) NPH-associated proteins grouped by their localization in steady-state cilia. (d) Transport of ciliary proteins by IFT components (green). The BBSome (orange) traffics receptors. Ciliary lipids (red) capture and retain specific proteins. Abbreviations: BBSome, protein complex involved in Bardet–Biedl syndrome; DAP, distal appendage; IFT, intraflagellar transport; JS, Joubert syndrome; MKS, Meckel syndrome; NPH, nephronophthisis; TZ, transition zone.

Figure 6

Mechanisms underlying ciliopathies. (a) Unique mechanisms underlying JS and BBS. (b) Diverse cellular dysfunction reported in the literature based on individual JS-MKS protein loss-of-function experiments across model organisms. Abbreviations: BBS, Bardet–Biedl syndrome; JS, Joubert syndrome; MKS, Meckel syndrome.