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

Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki MS, Abdel-Aleem A, Rosti RO, Kayserili H, Swistun D, Scott LC, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field SJ, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG - Nat. Genet. (2009)

Bottom Line: In individuals with Joubert disease genetically linked 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.These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.

View Article: PubMed Central - PubMed

Affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, USA.

ABSTRACT
Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked 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 by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.

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Missense mutations in the encoded enzymatic domain of INPP5E, (inositol polyphate-5-phosphatase E) in patients linked to the JBTS1 locus. (a) Top: axial brain MRIs showing molar tooth sign (red circle) from one affected from each linked family, representing four different countries of origin. Bottom: midline sagittal MRIs showing horizontally-oriented superior cerebellar peduncle (red arrow), not evident in control. Sequence chromatograms from one affected from each family, showing the nucleotide change (red arrow), with corresponding amino acid substitution listed below. Families MTI-007 and MTI-134 shared a common haplotype at the JBTS1 locus, as did COR-10 and COR-21, and they share common mutations. MTI-007 and MTI-134 have a compound homozygous mutation with a double R512W; R515W. (b) Predicted protein domains of INPP5E indicated by color. Each of the identified missense mutations (arrows) occurs in a basic residue within the catalytic domain and alters charge. (c) Evolutionary conservation of mutated amino acids.
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Figure 1: Missense mutations in the encoded enzymatic domain of INPP5E, (inositol polyphate-5-phosphatase E) in patients linked to the JBTS1 locus. (a) Top: axial brain MRIs showing molar tooth sign (red circle) from one affected from each linked family, representing four different countries of origin. Bottom: midline sagittal MRIs showing horizontally-oriented superior cerebellar peduncle (red arrow), not evident in control. Sequence chromatograms from one affected from each family, showing the nucleotide change (red arrow), with corresponding amino acid substitution listed below. Families MTI-007 and MTI-134 shared a common haplotype at the JBTS1 locus, as did COR-10 and COR-21, and they share common mutations. MTI-007 and MTI-134 have a compound homozygous mutation with a double R512W; R515W. (b) Predicted protein domains of INPP5E indicated by color. Each of the identified missense mutations (arrows) occurs in a basic residue within the catalytic domain and alters charge. (c) Evolutionary conservation of mutated amino acids.

Mentions: Joubert syndrome locus 1 (JBTS1, MIM%213300) was mapped to the distal q-arm of chromosome 9, between D9S1826-D9S1838 3, in two JS Emirate families variably associated with retinopathy, and a proven “molar tooth” sign (MTI-007 and MTI-008 previously called Family A and C, respectively, Fig. 1a, Supplemental Table 1) 3. To refine the candidate interval, we recruited two additional unaffected MTI-007 and two affected MTI-008 family members, and performed a 5K SNP analysis, confirming JBTS1 in MTI-007 (Supplemental Fig. 1). Family MTI-008 produced a linkage peak at JBTS1, among several other peaks of similar amplitude, with a maximum LOD score of about +1.94. As a result, these SNP scans failed to significantly narrow the candidate interval (Supplemental Table 2).


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

Bielas SL, Silhavy JL, Brancati F, Kisseleva MV, Al-Gazali L, Sztriha L, Bayoumi RA, Zaki MS, Abdel-Aleem A, Rosti RO, Kayserili H, Swistun D, Scott LC, Bertini E, Boltshauser E, Fazzi E, Travaglini L, Field SJ, Gayral S, Jacoby M, Schurmans S, Dallapiccola B, Majerus PW, Valente EM, Gleeson JG - Nat. Genet. (2009)

Missense mutations in the encoded enzymatic domain of INPP5E, (inositol polyphate-5-phosphatase E) in patients linked to the JBTS1 locus. (a) Top: axial brain MRIs showing molar tooth sign (red circle) from one affected from each linked family, representing four different countries of origin. Bottom: midline sagittal MRIs showing horizontally-oriented superior cerebellar peduncle (red arrow), not evident in control. Sequence chromatograms from one affected from each family, showing the nucleotide change (red arrow), with corresponding amino acid substitution listed below. Families MTI-007 and MTI-134 shared a common haplotype at the JBTS1 locus, as did COR-10 and COR-21, and they share common mutations. MTI-007 and MTI-134 have a compound homozygous mutation with a double R512W; R515W. (b) Predicted protein domains of INPP5E indicated by color. Each of the identified missense mutations (arrows) occurs in a basic residue within the catalytic domain and alters charge. (c) Evolutionary conservation of mutated amino acids.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2746682&req=5

Figure 1: Missense mutations in the encoded enzymatic domain of INPP5E, (inositol polyphate-5-phosphatase E) in patients linked to the JBTS1 locus. (a) Top: axial brain MRIs showing molar tooth sign (red circle) from one affected from each linked family, representing four different countries of origin. Bottom: midline sagittal MRIs showing horizontally-oriented superior cerebellar peduncle (red arrow), not evident in control. Sequence chromatograms from one affected from each family, showing the nucleotide change (red arrow), with corresponding amino acid substitution listed below. Families MTI-007 and MTI-134 shared a common haplotype at the JBTS1 locus, as did COR-10 and COR-21, and they share common mutations. MTI-007 and MTI-134 have a compound homozygous mutation with a double R512W; R515W. (b) Predicted protein domains of INPP5E indicated by color. Each of the identified missense mutations (arrows) occurs in a basic residue within the catalytic domain and alters charge. (c) Evolutionary conservation of mutated amino acids.
Mentions: Joubert syndrome locus 1 (JBTS1, MIM%213300) was mapped to the distal q-arm of chromosome 9, between D9S1826-D9S1838 3, in two JS Emirate families variably associated with retinopathy, and a proven “molar tooth” sign (MTI-007 and MTI-008 previously called Family A and C, respectively, Fig. 1a, Supplemental Table 1) 3. To refine the candidate interval, we recruited two additional unaffected MTI-007 and two affected MTI-008 family members, and performed a 5K SNP analysis, confirming JBTS1 in MTI-007 (Supplemental Fig. 1). Family MTI-008 produced a linkage peak at JBTS1, among several other peaks of similar amplitude, with a maximum LOD score of about +1.94. As a result, these SNP scans failed to significantly narrow the candidate interval (Supplemental Table 2).

Bottom Line: In individuals with Joubert disease genetically linked 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.These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.

View Article: PubMed Central - PubMed

Affiliation: Neurogenetics Laboratory, Howard Hughes Medical Institute, Department of Neurosciences and Pediatrics, University of California, San Diego, La Jolla, USA.

ABSTRACT
Phosphotidylinositol (PtdIns) signaling is tightly regulated both spatially and temporally by subcellularly localized PtdIns kinases and phosphatases that dynamically alter downstream signaling events. Joubert syndrome is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly and is included in the newly emerging group of 'ciliopathies'. In individuals with Joubert disease genetically linked 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 by Joubert syndrome, and mutations promoted premature destabilization of cilia in response to stimulation. These data link PtdIns signaling to the primary cilium, a cellular structure that is becoming increasingly recognized for its role in mediating cell signals and neuronal function.

Show MeSH
Related in: MedlinePlus