Mutations in INPP5E, encoding inositol polyphosphate-5-phosphatase E, link phosphatidyl inositol signaling to the ciliopathies

Abstract

Phosphotidylinositol (PtdIns) signaling is tightly regulated, both spatially and temporally, by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events 1. Joubert Syndrome (JS) characterized by a specific midbrain-hindbrain malformation (“molar tooth sign”) and variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly 2, and is included in the newly emerging group of “ciliopathies”. In patients linking to JBTS1, we identified mutations in the INPP5E gene, encoding inositol polyphosphate-5-phosphatase E, which hydrolyzes the 5-phosphate of PtdIns(3,4,5)P3 and PtdIns(4,5)P2. Mutations clustered in the phosphatase domain and impaired 5-phosphatase activity, resulting in altered cellular PtdIns ratios. INPP5E localized to cilia in major organs affected in JS, and mutations promoted premature destabilization of cilia in response to stimulation. Thus, these data links PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly appreciated for its role in mediating cell signals and neuronal function.

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

“…15 In particular, INPP5E has been shown to promote ciliary stabilization, and some mutations have been previously shown to alter the INPP5E enzymatic activity and promote premature cilia destabilization in response to specific stimuli. [10][11] Our data indicate a mutation prevalence of about 2.7% among JSRD, while no pathogenic changes were detected in 75 MKS fetuses, suggesting that INPP5E is not causative of the MKS phenotype. Lack of allelism between these two conditions has been already described for other ciliary genes such as ARL13B and CEP41, that are mutated only in JSRD.…”

“…Among JSRD, we identified 12 INPP5E mutations of which 10 novel, raising to 16 the number of distinct pathogenic changes so far reported. [10][11] We describe for the first time a homozygous nonsense mutation (p.Y543X), resulting in the production of a truncated protein lacking the final part of the catalytic domain and the C-terminus transmembrane domain. All the remaining mutations are missense changes affecting evolutionarily conserved amino-acid residues clustered within or flanking the enzymatically active phosphatase domain ( Figure 1).…”

“…Ten mutations were novel, whereas two (p.R435Q, pR563H) had been previously reported. 11 Mutations were homozygous in eight families and compound heterozygous in two. In COR28, only a single mutated allele was found, and genomic qPCR failed to identify deletions or duplications of INPP5E exons.…”

“…In the same year, we identified homozygous INPP5E mutations in seven consanguineous families genetically linked to the first JSRD locus (JBTS1) on 9q34. 11 To better define the phenotypic spectrum associated with INPP5E mutations and to evaluate their potential contribution to MKS, here we performed a comprehensive molecular screening of this gene in nearly 500 probands diagnosed with either JSRD or MKS.…”

Joubert syndrome: genotyping a Northern European patient cohort

“…Cystic kidney disease was present in only 2 of the 31 INPP5E-associated JBS cases with full clinical details reported in the literature. 21,22 Combining these data, the chance of cystic kidney disease in INPP5E-related JBS seems at least 10%. All other cases fit and consolidate the phenotypes that are proposed in the literature, 2,4 although some patients do not show the full clinical spectrum (possibly because of their young age).…”