Phenotypic spectrum and prevalence of INPP5E mutations in Joubert syndrome and related disorders

Abstract

Joubert syndrome and related disorders (JSRD) are clinically and genetically heterogeneous ciliopathies sharing a peculiar midbrain-hindbrain malformation known as the 'molar tooth sign'. To date, 19 causative genes have been identified, all coding for proteins of the primary cilium. There is clinical and genetic overlap with other ciliopathies, in particular with Meckel syndrome (MKS), that is allelic to JSRD at nine distinct loci. We previously identified the INPP5E gene as causative of JSRD in seven families linked to the JBTS1 locus, yet the phenotypic spectrum and prevalence of INPP5E mutations in JSRD and MKS remain largely unknown. To address this issue, we performed INPP5E mutation analysis in 483 probands, including 408 JSRD patients representative of all clinical subgroups and 75 MKS fetuses. We identified 12 different mutations in 17 probands from 11 JSRD families, with an overall 2.7% mutation frequency among JSRD. The most common clinical presentation among mutated families (7/11, 64%) was Joubert syndrome with ocular involvement (either progressive retinopathy and/or colobomas), while the remaining cases had pure JS. Kidney, liver and skeletal involvement were not observed. None of the MKS fetuses carried INPP5E mutations, indicating that the two ciliopathies are not allelic at this locus.

Figure 1

Mutations identified in INPP5E. (a) Axial magnetic resonance imaging from six probands with mutations in INPP5E, showing the MTS. (b) Schematic representation of the INPP5E protein consisting of four domains, including a proline rich domain, two small SH3 domains, a large conserved 300-amino-acid catalytic domain and a CAAX domain at C-terminus of the protein. Mutations identified in this article are reported above the panel, while previously described mutations are shown below (the only MORM-associated mutation in shown in italic). Recurrent mutations are shown in bold. (c) Conservation across species (shaded in yellow) of residues affected by the nine novel missense variants.