TTC21B contributes both causal and modifying alleles across the ciliopathy spectrum

被引：266

作者：

Davis, Erica E. ^{[1
,2
]}

Zhang, Qi ^{[3
]}

Liu, Qin ^{[3
]}

Diplas, Bill H. ^{[1
]}

Davey, Lisa M. ^{[1
]}

Hartley, Jane ^{[4
]}

Stoetzel, Corinne ^{[5
]}

Szymanska, Katarzyna ^{[6
]}

Ramaswami, Gokul ^{[7
]}

Logan, Clare V. ^{[6
]}

Muzny, Donna M. ^{[8
]}

Young, Alice C. ^{[9
]}

Wheeler, David A. ^{[8
]}

Cruz, Pedro ^{[9
]}

Morgan, Margaret ^{[8
]}

Lewis, Lora R. ^{[8
]}

Cherukuri, Praveen ^{[9
]}

Maskeri, Baishali ^{[9
]}

Hansen, Nancy F. ^{[9
]}

Mullikin, James C. ^{[9
]}

Blakesley, Robert W. ^{[9
]}

Bouffard, Gerard G. ^{[9
]}

Gyapay, Gabor ^{[10
]}

Rieger, Susanne ^{[11
]}

Toenshoff, Burkhard ^{[11
]}

Kern, Ilse ^{[12
]}

Soliman, Neveen A. ^{[13
]}

Neuhaus, Thomas J. ^{[14
]}

Swoboda, Kathryn J. ^{[15
,16
]}

Kayserili, Hulya ^{[17
]}

Gallagher, Tomas E. ^{[18
]}

Lewis, Richard A. ^{[19
,20
,21
,22
]}

Bergmann, Carsten ^{[23
,24
]}

Otto, Edgar A. ^{[7
]}

Saunier, Sophie ^{[25
]}

Scambler, Peter J. ^{[26
]}

Beales, Philip L. ^{[26
]}

Gleeson, Joseph G. ^{[27
]}

Maher, Eamonn R. ^{[4
]}

Attie-Bitach, Tania ^{[28
,29
]}

Dollfus, Helene ^{[5
]}

Johnson, Colin A. ^{[6
]}

Green, Eric D. ^{[9
]}

Gibbs, Richard A. ^{[8
]}

Hildebrandt, Friedhelm ^{[7
,30
,31
]}

Pierce, Eric A. ^{[3
]}

Katsanis, Nicholas ^{[1
,2
,32
,33
]}

机构：

[1] Duke Univ, Med Ctr, Dept Cell Biol, Ctr Human Dis Modeling, Durham, NC 27710 USA

[2] Duke Univ, Med Ctr, Dept Pediat, Durham, NC 27710 USA

[3] Univ Penn, Sch Med, FM Kirby Ctr Mol Ophthalmol, Philadelphia, PA 19104 USA

[4] Univ Birmingham, Inst Biomed Res, Dept Med & Mol Genet, Birmingham, W Midlands, England

[5] Univ Strasbourg, Avenir INSERM, Lab Genet Med EA3949, Strasbourg, France

[6] St James Univ Hosp, Sect Ophthalmol & Neurosci, Leeds Inst Mol Med, Leeds LS9 7TF, W Yorkshire, England

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

[8] Baylor Coll Med, Human Genome Sequencing Ctr, Houston, TX 77030 USA

[9] NHGRI, NIH, Intramural Sequencing Ctr, Bethesda, MD 20892 USA

[10] Genoscope Ctr Natl Sequencage, Evry, France

[11] Univ Childrens Hosp, Heidelberg, Germany

[12] Univ Hosp Geneva, Dept Pediat, Geneva, Switzerland

[13] Cairo Univ, Dept Pediat, Kasralainy Sch Med, Cairo, Egypt

[14] Univ Childrens Hosp Zurich, Div Nephrol, Zurich, Switzerland

[15] Univ Utah, Sch Med, Dept Neurol, Salt Lake City, UT USA

[16] Univ Utah, Sch Med, Dept Pediat, Salt Lake City, UT USA

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

[18] Univ Hawaii Manoa, Honolulu, HI 96822 USA

[19] Baylor Coll Med, Dept Ophthalmol, Houston, TX 77030 USA

[20] Baylor Coll Med, Dept Mol & Human Genet, Houston, TX 77030 USA

[21] Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA

[22] Baylor Coll Med, Dept Med, Houston, TX 77030 USA

[23] Bioscientia, Ctr Human Genet, Ingelheim, Germany

[24] Rhein Westfal TH Aachen, Dept Human Genet, Aachen, Germany

[25] Univ Paris 05, Hop Necker Enfants Malades, INSERM, U983, Paris, France

[26] UCL, Mol Med Unit, Inst Child Hlth, London, England

[27] Univ Calif San Diego, Howard Hughes Med Inst, Dept Neurosci, La Jolla, CA 92093 USA

[28] Univ Paris 05, Hop Necker Enfants Malades, INSERM, U781, Paris, France

[29] Univ Paris 05, Hop Necker Enfants Malades, Dept Genet, Paris, France

[30] Howard Hughes Med Inst, Ann Arbor, MI USA

[31] Univ Michigan, Dept Human Genet, Ann Arbor, MI 48109 USA

[32] Johns Hopkins Univ, Sch Med, Wilmer Eye Inst, Baltimore, MD 21205 USA

[33] Johns Hopkins Univ, Sch Med, Dept Mol Biol & Genet, Baltimore, MD 21205 USA

来源：

NATURE GENETICS | 2011年 / 43卷 / 03期

基金：

美国国家卫生研究院; 英国医学研究理事会;

关键词：

BARDET-BIEDL-SYNDROME; RETROGRADE INTRAFLAGELLAR TRANSPORT; JOUBERT-SYNDROME; RETINAL DEGENERATION; CENTROSOMAL PROTEIN; MECKEL-SYNDROME; IN-VIVO; MUTATIONS; GENE; NEPHRONOPHTHISIS;

D O I：

10.1038/ng.756

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Ciliary dysfunction leads to a broad range of overlapping phenotypes, collectively termed ciliopathies. This grouping is underscored by genetic overlap, where causal genes can also contribute modifier alleles to clinically distinct disorders. Here we show that mutations in TTC21B, which encodes the retrograde intraflagellar transport protein IFT139, cause both isolated nephronophthisis and syndromic Jeune asphyxiating thoracic dystrophy. Moreover, although resequencing of TTC21B in a large, clinically diverse ciliopathy cohort and matched controls showed a similar frequency of rare changes, in vivo and in vitro evaluations showed a significant enrichment of pathogenic alleles in cases (P < 0.003), suggesting that TTC21B contributes pathogenic alleles to similar to 5% of ciliopathy cases. Our data illustrate how genetic lesions can be both causally associated with diverse ciliopathies and interact in trans with other disease-causing genes and highlight how saturated resequencing followed by functional analysis of all variants informs the genetic architecture of inherited disorders.

引用

页码：189 / U28

页数：10

共 31 条

[1] Basal body dysfunction is a likely cause of pleiotropic Bardet-Biedl syndrome [J].

Ansley, SJ ;

Badano, JL ;

Blacque, OE ;

Hill, J ;

Hoskins, BE ;

Leitch, CC ;

Kim, JC ;

Ross, AJ ;

Eichers, ER ;

Teslovich, TM ;

Mah, AK ;

Johnsen, RC ;

Cavender, JC ;

Lewis, RA ;

Leroux, MR ;

Beales, PL ;

Katsanis, N .

NATURE, 2003, 425 (6958) :628-633

[2] Pleiotropic effects of CEP290 (NPHP6) mutations extend to Meckel syndrome [J].

Baala, Lekbir ;

Audollent, Sophie ;

Martinovic, Jelena ;

Ozilou, Catherine ;

Babron, Marie-Claude ;

Sivanandamoorthy, Sivanthiny ;

Saunier, Sophie ;

Salomon, Remi ;

Gonzales, Marie ;

Rattenberry, Eleanor ;

Esculpavit, Chantal ;

Toutain, Annick ;

Moraine, Claude ;

Parent, Philippe ;

Marcorelles, Pascale ;

Dauge, Marie-Christine ;

Roume, Joelle ;

Le Merrer, Martine ;

Meiner, Vardiella ;

Meir, Karen ;

Menez, Francoise ;

Beaufrere, Anne-Marie ;

Francannet, Christine ;

Tantau, Julia ;

Sinico, Martine ;

Dumez, Yves ;

MacDonald, Fiona ;

Munnich, Arnold ;

Lyonnet, Stanislas ;

Gubler, Marie-Claire ;

Genin, Emmanuelle ;

Johnson, Colin A. ;

Vekemans, Michel ;

Encha-Razavi, Ferechte ;

Attie-Bitach, Tania .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 81 (01) :170-179

[3] The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome [J].

Baala, Lekbir ;

Romano, Stephane ;

Khaddour, Rana ;

Saunier, Sophie ;

Smith, Ursula M. ;

Audollent, Sophie ;

Ozilou, Catherine ;

Faivre, Laurence ;

Laurent, Nicole ;

Foliguet, Bernard ;

Munnich, Arnold ;

Lyonnet, Stanislas ;

Salomon, Remi ;

Encha-Razavi, Ferechte ;

Gubler, Marie-Claire ;

Boddaert, Nathalie ;

de Lonlay, Pascale ;

Johnson, Colin A. ;

Vekemans, Michel ;

Antignac, Corinne ;

Attie-Bitach, Tania .

AMERICAN JOURNAL OF HUMAN GENETICS, 2007, 80 (01) :186-194

[4] Dissection of epistasis in oligogenic Bardet-Biedl syndrome [J].

Badano, JL ;

Leitch, CC ;

Ansley, SJ ;

May-Simera, H ;

Lawson, S ;

Lewis, RA ;

Beales, PL ;

Dietz, HC ;

Fisher, S ;

Katsanis, N .

NATURE, 2006, 439 (7074) :326-330

[5] The ciliopathies: An emerging class of human genetic disorders [J].

Badano, Jose L. ;

Mitsuma, Norimasa ;

Beales, Phil L. ;

Katsanis, Nicholas .

ANNUAL REVIEW OF GENOMICS AND HUMAN GENETICS, 2006, 7 :125-148

[6]

Beales PL, 1999, J MED GENET, V36, P437

[7] Loss of nephrocystin-3 function can cause embryonic lethality, meckel-gruber-like syndrome, situs inversus, and renal-hepatic-pancreatic dysplasia [J].

Bergmann, Carsten ;

Fliegauf, Manfred ;

Bruechle, Nadina Ortiz ;

Frank, Valeska ;

Olbrich, Heike ;

Kirschner, Jan ;

Schermer, Bernhard ;

Schmedding, Ingolf ;

Kispert, Andreas ;

Kraenzlin, Bettina ;

Nuernberg, Gudrun ;

Becker, Christian ;

Grimm, Tiemo ;

Girschick, Gundula ;

Lynch, Sally A. ;

Kelehan, Peter ;

Senderek, Jan ;

Neuhaus, Thomas J. ;

Stallmach, Thomas ;

Zentgraf, Hanswalter ;

Nuernberg, Peter ;

Gretz, Norbert ;

Lo, Cecilia ;

Lienkamp, Soeren ;

Schaefer, Tobias ;

Walz, Gerd ;

Benzing, Thomas ;

Zerres, Klaus ;

Omran, Heymut .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (04) :959-970

[8] The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome [J].

Delous, Marion ;

Baala, Lekbir ;

Salomon, Remi ;

Laclef, Christine ;

Vierkotten, Jeanette ;

Tory, Kalman ;

Golzio, Christelle ;

Lacoste, Tiphanie ;

Besse, Laurianne ;

Ozilou, Catherine ;

Moutkine, Imane ;

Hellman, Nathan E. ;

Anselme, Isabelle ;

Silbermann, Flora ;

Vesque, Christine ;

Gerhardt, Christoph ;

Rattenberry, Eleanor ;

Wolf, Matthias T. F. ;

Gubler, Marie Claire ;

Martinovic, Jelena ;

Encha-Razavi, Ferechte ;

Boddaert, Nathalie ;

Gonzales, Marie ;

Macher, Marie Alice ;

Nivet, Hubert ;

Champion, Gerard ;

Bertheleme, Jean Pierre ;

Niaudet, Patrick ;

McDonald, Fiona ;

Hildebrandt, Friedhelm ;

Johnson, Colin A. ;

Vekemans, Michel ;

Antignac, Corinne ;

Ruether, Ulrich ;

Schneider-Maunoury, Sylvie ;

Attie-Bitach, Tania ;

Saunier, Sophie .

NATURE GENETICS, 2007, 39 (07) :875-881

[9] The ciliary proteome database: an integrated community resource for the genetic and functional dissection of cilia [J].

Gherman, Adrian ;

Davis, Erica E. ;

Katsanis, Nicholas .

NATURE GENETICS, 2006, 38 (09) :961-962

[10] CC2D2A Is Mutated in Joubert Syndrome and Interacts with the Ciliopathy-Associated Basal Body Protein CEP290 [J].

Gorden, Nicholas T. ;

Arts, Heleen H. ;

Parisi, Melissa A. ;

Coene, Karlien L. M. ;

Letteboer, Stef J. F. ;

van Beersum, Sylvia E. C. ;

Mans, Dorus A. ;

Hikida, Abigail ;

Eckert, Melissa ;

Knutzen, Dana ;

Alswaid, Abdulrahman F. ;

Ozyurek, Hamit ;

Dibooglu, Sel ;

Otto, Edgar A. ;

Liu, Yangfan ;

Davis, Erica E. ;

Hutter, Carolyn M. ;

Bammler, Theo K. ;

Farin, Frederico M. ;

Dorschner, Michael ;

Topcu, Meral ;

Zackai, Elaine H. ;

Rosenthal, Phillip ;

Owens, Kelly N. ;

Katsanis, Nicholas ;

Vincent, John B. ;

Hildebrandt, Friedhelm ;

Rubel, Edwin W. ;

Raible, David W. ;

Knoers, Nine V. A. M. ;

Chance, Phillip F. ;

Roepman, Ronald ;

Moens, Cecilia B. ;

Glass, Ian A. ;

Doherty, Dan .

AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 83 (05) :559-571

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