Defects in the IFT-B Component IFT172 Cause Jeune and Mainzer-Saldino Syndromes in Humans

被引：177

作者：

Halbritter, Jan ^{[1
,2
]}

Bizet, Albane A. ^{[3
,4
]}

Schmidts, Miriam ^{[5
,6
]}

Porath, Jonathan D. ^{[1
,2
]}

Braun, Daniela A. ^{[1
,2
]}

Gee, Heon Yung ^{[1
,2
]}

McInerney-Leo, Aideen M. ^{[7
]}

Krug, Pauline ^{[3
,4
]}

Filhol, Emilie ^{[3
,4
]}

Davis, Erica E. ^{[8
]}

Airik, Rannar ^{[1
,2
]}

Czarnecki, Peter G. ^{[9
,10
,11
]}

Lehman, Anna M. ^{[12
]}

Trnka, Peter ^{[13
]}

Nitschke, Patrick ^{[14
]}

Bole-Feysot, Christine ^{[15
]}

Schueler, Markus ^{[1
,2
]}

Knebelmann, Bertrand ^{[16
]}

Burtey, Stephane ^{[17
]}

Szabo, Attila J. ^{[18
]}

Tory, Kalman ^{[3
,18
]}

Leo, Paul J. ^{[7
]}

Gardiner, Brooke ^{[7
]}

McKenzie, Fiona A. ^{[19
,20
]}

Zankl, Andreas ^{[7
,21
,22
,23
]}

Brown, Matthew A. ^{[7
]}

Hartley, Jane L. ^{[24
]}

Maher, Eamonn R. ^{[25
,26
]}

Li, Chunmei ^{[27
]}

Leroux, Michel R. ^{[27
]}

Scambler, Peter J. ^{[5
,6
]}

Zhan, Shing H. ^{[28
]}

Jones, Steven J. ^{[12
,28
]}

Kayserili, Hulya ^{[29
]}

Tuysuz, Beyhan ^{[30
]}

Moorani, Khemchand N. ^{[31
]}

Constantinescu, Alexandru ^{[32
]}

Krantz, Ian D. ^{[33
]}

Kaplan, Bernard S. ^{[34
]}

Shah, Jagesh V. ^{[9
,11
,35
]}

Hurd, Toby W. ^{[36
]}

Doherty, Dan ^{[37
]}

Katsanis, Nicholas ^{[8
]}

Duncan, Emma L. ^{[7
,20
,38
]}

Otto, Edgar A.

Beales, Philip L. ^{[5
,6
]}

Mitchison, Hannah M. ^{[5
,6
]}

Saunier, Sophie ^{[3
,4
]}

Hildebrandt, Friedhelm ^{[1
,2
,39
]}

机构：

[1] Boston Childrens Hosp, Dept Med, Div Nephrol, Boston, MA 02115 USA

[2] Harvard Univ, Sch Med, Boston, MA 02115 USA

[3] Hop Necker Enfants Malad, INSERM, U983, F-75015 Paris, France

[4] Paris Descartes Univ, Imagine Inst, Sorbonne Paris Cite, F-75015 Paris, France

[5] UCL, Inst Child Hlth, Mol Med Unit, London WC1N 1EH, England

[6] UCL, Inst Child Hlth, Birth Defects Res Ctr, London WC1N 1EH, England

[7] Univ Queensland, Diamantina Inst, Translat Res Inst, Woolloongabba, Qld 4102, Australia

[8] Duke Univ, Ctr Human Dis Modeling, Durham, NC 27710 USA

[9] Harvard Univ, Sch Med, Dept Syst Biol, Boston, MA 02115 USA

[10] Beth Israel Deaconess Med Ctr, Dept Med, Div Nephrol, Boston, MA 02215 USA

[11] Harvard MIT Hlth Sci & Technol, Cambridge, MA 02139 USA

[12] Univ British Columbia, Dept Med Genet, Vancouver, BC V6H 3N1, Canada

[13] Univ Queensland, Sch Paediat & Child Hlth, Herston, Qld 4029, Australia

[14] Paris Descartes Univ, Sorbonne Paris Cite, Bioinformat Platform, F-75270 Paris, France

[15] Imagine Inst, Genom Platform, F-75015 Paris, France

[16] Hop Necker Enfants Malad, AP HP, Dept Nephrol, F-75015 Paris, France

[17] Hop Conception, Ctr Nephrol & Transplantat Renale, F-13005 Marseille, France

[18] Semmelweis Univ, Dept Pediat 1, H-1083 Budapest, Hungary

[19] Genet Serv Western Australia, Subiaco, WA 6008, Australia

[20] Univ Western Australia, Sch Paediat & Child Hlth, Crawley, WA 6009, Australia

[21] Univ Queensland, UQ Ctr Clin Res, Herston, Qld 4029, Australia

[22] Univ Sydney, Sydney, NSW 2006, Australia

[23] Childrens Hosp Westmead, Acad Dept Med Genet, Sydney, NSW 2145, Australia

[24] Birmingham Childrens Hosp, Birmingham B4 6NH, W Midlands, England

[25] Univ Birmingham, Ctr Rare Dis & Personalised Med, Birmingham B15 2TT, W Midlands, England

[26] Univ Cambridge, Dept Med Genet, Cambridge CB2 0QQ, England

[27] Simon Fraser Univ, Dept Mol Biol & Biochem, Burnaby, BC V5A 1S6, Canada

[28] British Columbia Canc Agcy, Genome Sci Ctr, Vancouver, BC V5Z 4S6, Canada

[29] Istanbul Univ, Istanbul Fac Med, Dept Med Genet, TR-34093 Istanbul, Turkey

[30] Istanbul Univ, Cerrahpasa Med Sch, Dept Pediat, Div Pediat Genet, TR-34098 Istanbul, Turkey

[31] Natl Inst Child Hlth, Dept Paediat Nephrol, Karachi 75510, Pakistan

[32] Joe DiMaggio Childrens Hosp, Div Pediat Nephrol, Hollywood, FL 33021 USA

[33] Childrens Hosp Philadelphia, Div Human Genet, Philadelphia, PA 19104 USA

[34] Childrens Hosp Philadelphia, Div Nephrol, Philadelphia, PA 19104 USA

[35] Brigham & Womens Hosp, Boston, MA 02215 USA

[36] Univ Michigan, Dept Pediat, Ann Arbor, MI 48109 USA

[37] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[38] Royal Brisbane & Womens Hosp, Dept Endocrinol, Herston, Qld 4029, Australia

[39] Howard Hughes Med Inst, Chevy Chase, MD USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2013年 / 93卷 / 05期

基金：

美国国家卫生研究院; 英国惠康基金;

关键词：

ASPHYXIATING THORACIC DYSTROPHY; INTRAFLAGELLAR TRANSPORT PROTEIN; RIB-POLYDACTYLY SYNDROME; VAN-CREVELD-SYNDROME; DYNC2H1; MUTATIONS; CILIOPATHY; DISEASE; GENE; CILIA; KIDNEY;

D O I：

10.1016/j.ajhg.2013.09.012

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Intraflagellar transport (IFT) depends on two evolutionarily conserved modules, subcomplexes A (IFT-A) and B (IFT-B), to drive ciliary assembly and maintenance. All six IFT-A components and their motor protein, DYNC2H1, have been linked to human skeletal ciliopathies, including asphyxiating thoracic dystrophy (ATD; also known as Jeune syndrome), Sensenbrenner syndrome, and Mainzer-Saldino syndrome (MZSDS). Conversely, the 14 subunits in the IFT-B module, with the exception of IFT80, have unknown roles in human disease. To identify additional IFT-B components defective in ciliopathies, we independently performed different mutation analyses: candidate-based sequencing of all IFT-B-encoding genes in 1,467 individuals with a nephronophthisis-related ciliopathy or whole-exome resequencing in 63 individuals with ATD. We thereby detected biallelic mutations in the IFT-B-encoding gene IFT172 in 12 families. All affected individuals displayed abnormalities of the thorax and/or long bones, as well as renal, hepatic, or retinal involvement, consistent with the diagnosis of ATD or MZSDS. Additionally, cerebellar aplasia or hypoplasia characteristic of Joubert syndrome was present in 2 out of 12 families. Fibroblasts from affected individuals showed disturbed ciliary composition, suggesting alteration of ciliary transport and signaling. Knockdown of ift172 in zebrafish recapitulated the human phenotype and demonstrated a genetic interaction between ift172 and ift80. In summary, we have identified defects in IFT172 as a cause of complex ATD and MZSDS. Our findings link the group of skeletal ciliopathies to an additional IFT-B component, IFT172, similar to what has been shown for IFT-A.

引用

页码：915 / 925

页数：11

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