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

Travaglini, Lorena; Brancati, Francesco; Silhavy, Jennifer L.; Iannicelli, Miriam; Nickerson, Elizabeth; Elkhartoufi, Nadia; Scott, Eric; Spencer, Emily; Gabriel, Stacey; Thomas, Sophie; Ben‐Zeev, Bruria; Bertini, Enrico; Boltshauser, Eugen; Chaouch, Malika; Cilio, Maria Roberta; Jong, Mirjam M. de; Kayserili, Hülya; Oğur, Gönül; Poretti, Andrea; Signorini, Sabrina; Uziel, Graziella; Zaki, Maha S.; Johnson, Colin A.; Attié‐Bitach, Tania; Gleeson, Joseph G.; Valente, Enza Maria

doi:10.1038/ejhg.2012.305

Cited by 64 publications

(69 citation statements)

References 28 publications

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“…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).…”

Section: Genotype-phenotype Correlationsmentioning

confidence: 96%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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Joubert syndrome (JBS) is a rare neurodevelopmental disorder belonging to the group of ciliary diseases. JBS is genetically heterogeneous, with 420 causative genes identified to date. A molecular diagnosis of JBS is essential for prediction of disease progression and genetic counseling. We developed a targeted next-generation sequencing (NGS) approach for parallel sequencing of 22 known JBS genes plus 599 additional ciliary genes. This method was used to genotype a cohort of 51 well-phenotyped Northern European JBS cases (in some of the cases, Sanger sequencing of individual JBS genes had been performed previously). Altogether, 21 of the 51 cases (41%) harbored biallelic pathogenic mutations in known JBS genes, including 14 mutations not previously described. Mutations in C5orf42 (12%), TMEM67 (10%), and AHI1 (8%) were the most prevalent. C5orf42 mutations result in a purely neurological Joubert phenotype, in one case associated with postaxial polydactyly. Our study represents a population-based cohort of JBS patients not enriched for consanguinity, providing insight into the relative importance of the different JBS genes in a Northern European population. Mutations in C5orf42 are relatively frequent (possibly due to a Dutch founder mutation) and mutations in CEP290 are underrepresented compared with international cohorts. Furthermore, we report a case with heterozygous mutations in CC2D2A and B9D1, a gene associated with the more severe Meckel-Gruber syndrome that was recently published as a potential new JBS gene, and discuss the significance of this finding.

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Section: Genotype-phenotype Correlationsmentioning

confidence: 96%

Joubert syndrome: genotyping a Northern European patient cohort

et al. 2015

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“…Most INPP5E missense mutations causative of Joubert syndrome affect the catalytic domain of the protein, impairing its enzymatic activity. 85,99 Although the ability of the mutated Inpp5E to localize in the cilium is not compromised, cells bearing these INPP5E mutations exhibit greater PC instability and are more sensitive to serum-stimulated cilium disassembly. 85 Further, mice models lacking Inpp5E show embryonic lethality, displaying renal cysts and neurological defects at early stages of development but with very mild or no ocular defects.…”

Section: Diseases Associated With Mutations In Inpp5ementioning

confidence: 99%

“…32,85,99 Evidence indicates that Inpp5E is required to regulate phosphoinositide metabolism inside the PC and is particularly critical for the tight regulation of the PDGF-PI3K-Akt pathway, which mediates cell cycle entry. 85 The only INPP5E mutation identified to cause MORM syndrome (Q627X) is a nonsense mutation that renders a truncated Inpp5E protein lacking the CAAX box at the C-terminus.…”

mentioning

confidence: 99%

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Madhivanan¹,

Ramadesika²,

Aguilar

2016

RRB

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Abstract:The primary cilium (PC) is a plasma membrane-derived structure of great importance for cell and organismal physiology. Indeed, abnormalities in assembly or function of the PC trigger the onset of a group of genetic diseases collectively known as ciliopathies. In recent years, it has become evident that the integrity and function of the PC depends substantially on signaling elements such as phosphoinositides (PI) and their regulators. Because phospholipids such as PI(4,5)P 2 constitute recruitment platforms for cytoskeleton, signaling, and trafficking machinery, control over their levels is critical for PC function. Although information about phosphoinositol phosphate (PIP) kinases in the PC is scarce, a growing body of evidence supports a role for PIP phosphatases in cilia assembly/maintenance. Indeed, deficiencies in two 5′ PIP phosphatases, Inpp5E and Ocrl1, are clearly linked to ciliopathies like Joubert/MORM syndromes, or ciliopathy-associated dise ases like Lowe syndrome. Here, we review the unique roles of these proteins and their specific site of action for ensuring ciliary integrity. Further, we discuss the possibility that a phosphatase relay system able to pass PI control from a preciliary to an intraciliary compartment is in place to ensure PC integrity/function.

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“…Indeed both PDE6D and INPP5E are disease genes in Joubert syndrome, a neurodevelopmental ciliopathy clinically defined as the presence of a "molar tooth sign" on axial MRI alongside one or more classic ciliopathy presentations [11,12]. Mutations in INPP5E have been reported in a number of JBTS patients [11,13] throughout the gene; widely in the phosphatase domain, but also in the CAAX domain, required for interaction with PDE6D, and the SH3 domain, required for interaction with Arl13b [13][14][15] suggesting the importance of GSF trafficking in healthy ciliogenesis.…”

Section: Gdi-like Solubilizing Factors (Gsfs)mentioning

confidence: 99%

Shuttling and sorting lipid-modified cargo into the cilia

Stephen

Ismail

2016

Biochemical Society Transactions

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Primary cilia are hair-like microtubule-based organelles that can be found on almost all human cell types. Although the cilium is not separated from the cell by membranes, their content is different from that of the cell body and their membrane composition is distinct from that of the plasma membrane. Here we will introduce a molecular machinery that shuttles and sorts lipid modified proteins to the cilium, thus contributing in maintaining its distinct composition. The mechanism involves the binding of the GDI-like solubilising factors, UNC119a, UNC119b and PDE6D, to the lipid modified ciliary cargo and the specific release of the cargo in the cilia by the ciliary small G protein Arl3 in a GTP dependent manner.

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

Cited by 64 publications

References 28 publications

Joubert syndrome: genotyping a Northern European patient cohort

Joubert syndrome: genotyping a Northern European patient cohort

Role of Ocrl1 and Inpp5E in primary cilia assembly and maintenance: a phosphatidylinositol phosphatase relay system?

Shuttling and sorting lipid-modified cargo into the cilia

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