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

被引：323

作者：

Bielas, Stephanie L. ^{[1
]}

Silhavy, Jennifer L. ^{[1
]}

Brancati, Francesco ^{[2
,3
,4
]}

Kisseleva, Marina V. ^{[5
]}

Al-Gazali, Lihadh ^{[6
,7
]}

Laszlo Sztriha ^{[8
]}

Bayoumi, Riad A. ^{[9
]}

Zaki, Maha S. ^{[10
]}

Abdel-Aleem, Alice ^{[11
]}

Rosti, Rasim Ozgur ^{[12
]}

Kayserili, Hulya ^{[12
]}

Swistun, Dominika ^{[1
]}

Scott, Lesley C. ^{[1
]}

Bertini, Enrico ^{[13
]}

Boltshauser, Eugen ^{[14
]}

Fazzi, Elisa ^{[15
]}

Travaglini, Lorena ^{[2
]}

Field, Seth J. ^{[16
]}

Gayral, Stephanie ^{[17
]}

Jacoby, Monique ^{[17
]}

Schurmans, Stephane ^{[17
]}

Dallapiccola, Bruno ^{[2
,18
]}

Majerus, Philip W. ^{[5
]}

Valente, Enza Maria ^{[2
,19
]}

Gleeson, Joseph G. ^{[1
]}

机构：

[1] Univ Calif San Diego, Howard Hughes Med Inst, Neurogenet Lab, Dept Neurosci & Pediat, La Jolla, CA 92093 USA

[2] Casa Sollievo Sofferenza Hosp, Casa Sollievo Sofferenza Mendel Inst, Rome, Italy

[3] G Annunzio Univ Fdn, Dept Biomed Sci, Ctr Studi Invecchiamento, Chieti, Italy

[4] G Annunzio Univ Fdn, Aging Res Ctr, Ctr Studi Invecchiamento, Chieti, Italy

[5] Washington Univ, Sch Med, Dept Internal Med, Div Hematol, St Louis, MO 63110 USA

[6] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Pediat, Al Ain, U Arab Emirates

[7] United Arab Emirates Univ, Fac Med & Hlth Sci, Dept Pathol, Al Ain, U Arab Emirates

[8] Univ Szeged, Dept Pediat, Szeged, Hungary

[9] Sultan Qaboos Univ, Coll Med, Al Khoud, Oman

[10] Natl Res Ctr, Dept Clin Genet, Cairo, Egypt

[11] Natl Res Ctr, Med Mol Genet Dept, Human Genet & Genome Res Div, Cairo, Egypt

[12] Istanbul Univ, Istanbul Fac Med, Istanbul, Turkey

[13] Bambino Gesu Childrens Res Hosp, Mol Med Unit, Dept Lab Med, Rome, Italy

[14] Univ Childrens Hosp Zurich, Dept Paediat Neurol, Zurich, Switzerland

[15] Dept Child Neurol & Psychiat, Pavia, Italy

[16] Univ Calif San Diego, Dept Med, Div Endocrinol & Metab, La Jolla, CA 92093 USA

[17] Univ Libre Bruxelles, IRIBHM, IBMM, Gosselies, Belgium

[18] Univ Roma La Sapienza, Dept Expt Med, I-00185 Rome, Italy

[19] Univ Messina, Dept Med & Surg Paediat Sci, Messina, Italy

来源：

NATURE GENETICS | 2009年 / 41卷 / 09期

基金：

美国国家卫生研究院;

关键词：

JOUBERT-SYNDROME; POLYPHOSPHATE; 5-PHOSPHATASE; MEMBRANE; PROTEIN; 3-PHOSPHATE; CEP290; FORMS; RAB8;

D O I：

10.1038/ng.423

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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 is characterized by a specific midbrain-hindbrain malformation ('molar tooth sign'), variably associated retinal dystrophy, nephronophthisis, liver fibrosis and polydactyly(2) 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.

引用

页码：1032 / U108

页数：6

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