Differential Contributions of Rare and Common, Coding and Noncoding Ret Mutations to Multifactorial Hirschsprung Disease Liability

被引:204
作者
Emison, Eileen Sproat [1 ]
Garcia-Barcelo, Merce [2 ]
Grice, Elizabeth A. [1 ]
Lantieri, Francesca [3 ,4 ]
Amiel, Jeanne [5 ,6 ]
Burzynski, Grzegorz [7 ]
Fernandez, Raquel M. [8 ,9 ]
Hao, Li [1 ]
Kashuk, Carl [1 ]
West, Kristen [1 ]
Miao, Xiaoping [2 ]
Tam, Paul K. H. [2 ]
Griseri, Paola [4 ]
Ceccherini, Isabella [4 ]
Pelet, Anna [5 ,6 ]
Jannot, Anne-Sophie [5 ,6 ,10 ]
de Pontual, Loic [5 ,6 ]
Henrion-Caude, Alexandra [5 ,6 ]
Lyonnet, Stanislas [5 ,6 ]
Verheij, Joke B. G. M. [7 ]
Hofstra, Robert M. W. [7 ]
Antinolo, Guillermo [8 ,9 ]
Borrego, Salud [8 ,9 ]
McCallion, Andrew S. [1 ]
Chakravarti, Aravinda [1 ]
机构
[1] Johns Hopkins Univ, Sch Med, Ctr Complex Dis Genom, McKusick Nathans Inst Genet Med, Baltimore, MD 21205 USA
[2] Univ Hong Kong, Dept Surg, Pokfulam, Hong Kong, Peoples R China
[3] Univ Genoa, Dept Hlth Sci, Biostat Unit, I-16126 Genoa, Italy
[4] Ist Giannina Gaslini, Mol Genet Lab, I-16147 Genoa, Italy
[5] Univ Paris 05, Fac Med, Dept Genet, F-75006 Paris, France
[6] Hop Necker Enfants Malad, AP HP, INSERM, U781, F-78743 Paris, France
[7] Univ Groningen, Dept Med Genet, NL-9700 Groningen, Netherlands
[8] Hosp Univ Virgen Rocio, Unidad Gest Clin Genet Reprod & Med Fetal, Seville 41013, Spain
[9] ISCIII, CIBERER, Seville 41013, Spain
[10] INSERM, U535, F-94817 Villejuif, France
基金
美国国家卫生研究院;
关键词
TRANSCRIPTION FACTOR SOX10; LINKAGE DISEQUILIBRIUM; GENE-EXPRESSION; C-RET; PROTOONCOGENE; ENHANCER; DNA; ASSOCIATION; HAPLOTYPE; PROTEIN;
D O I
10.1016/j.ajhg.2010.06.007
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
The major gene for Hirschsprung disease (HSCR) encodes the receptor tyrosine kinase RET. In a study of 690 European- and 192 Chinese-descent probands and their parents or controls, we demonstrate the ubiquity of a >4-fold susceptibility from a C -> T allele (rs2435357: p = 3.9 x 10(-43) in European ancestry; p = 1.1 x 10(-21) in Chinese samples) that probably arose once within the intronic RET enhancer MCS+9.7. With in vitro assays, we now show that the T variant disrupts a SOX10 binding site within MCS+9.7 that compromises RET transactivation. The T allele, with a control frequency of 20%-30%/47% and case frequency of 54%-62%/88% in European/Chinese-ancestry individuals, is involved in all forms of HSCR. It is marginally associated with proband gender (p = 0.13) and significantly so with length of aganglionosis (p = 7.6 x 10(-5)) and familiality (p = 6.2 x 10(-4)). The enhancer variant is more frequent in the common forms of male, short-segment, and simplex families whereas multiple, rare, coding mutations are the norm in the less common and more severe forms of female, long-segment, and multiplex families. The T variant also increases penetrance in patients with rare RET coding mutations. Thus, both rare and common mutations, individually and together, make contributions to the risk of HSCR. The distribution of RET variants in diverse HSCR patients suggests a "cellular-recessive" genetic model where both RET alleles' function is compromised. The RET allelic series, and its genotype-phenotype correlations, shows that success in variant identification in complex disorders may strongly depend on which patients are studied.
引用
收藏
页码:60 / 74
页数:15
相关论文
共 43 条
[1]   GOLD - Graphical Overview of Linkage Disequilibrium [J].
Abecasis, GR ;
Cookson, WOC .
BIOINFORMATICS, 2000, 16 (02) :182-183
[2]  
Altenburg E, 1920, GENETICS, V5, P1
[3]   Genetic Mapping in Human Disease [J].
Altshuler, David ;
Daly, Mark J. ;
Lander, Eric S. .
SCIENCE, 2008, 322 (5903) :881-888
[4]   Hirschsprung disease, associated syndromes and genetics: a review [J].
Amiel, J. ;
Sproat-Emison, E. ;
Garcia-Barcelo, M. ;
Lantieri, F. ;
Burzynski, G. ;
Borrego, S. ;
Pelet, A. ;
Arnold, S. ;
Miao, X. ;
Griseri, P. ;
Brooks, A. S. ;
Antinolo, G. ;
de Pontual, L. ;
Clement-Ziza, M. ;
Munnich, A. ;
Kashuk, C. ;
West, K. ;
Wong, K. K-Y ;
Lyonnet, S. ;
Chakravarti, A. ;
Tam, P. K-H ;
Ceccherini, I. ;
Hofstra, R. M. W. ;
Fernandez, R. .
JOURNAL OF MEDICAL GENETICS, 2008, 45 (01) :1-14
[5]  
[Anonymous], 2001, The Metabolic and Molecular Bases of Inherited Disease
[6]   Interaction Between a Chromosome 10 RET Enhancer and Chromosome 21 in the Down Syndrome-Hirschsprung Disease Association [J].
Arnold, Stacey ;
Pelet, Anna ;
Amiel, Jeanne ;
Borrego, Salud ;
Hofstra, Robert ;
Tam, Paul ;
Ceccherini, Isabella ;
Lyonnet, Stanislas ;
Sherman, Stephanie ;
Chakravarti, Aravinda .
HUMAN MUTATION, 2009, 30 (05) :771-775
[7]  
BADNER JA, 1990, AM J HUM GENET, V46, P568
[8]   A FAMILY STUDY OF HIRSCHSPRUNGS DISEASE [J].
BODIAN, M ;
CARTER, CO .
ANNALS OF HUMAN GENETICS, 1963, 26 (03) :261-277
[9]   Basal laminar drusen caused by compound heterozygous variants in the CFH gene [J].
Boon, Camiel J. E. ;
Klevering, B. Jeroen ;
Hoyng, Carel B. ;
Zonneveld-Vrieling, Marijke N. ;
Nabuurs, Sander B. ;
Blokland, Ellen ;
Cremers, Frans P. M. ;
den Hollander, Anneke I. .
AMERICAN JOURNAL OF HUMAN GENETICS, 2008, 82 (02) :516-523
[10]   Specific polymorphisms in the RET proto-oncogene are over-represented in patients with Hirschsprung disease and may represent loci modifying phenotypic expression [J].
Borrego, S ;
Sáez, ME ;
Ruiz, A ;
Gimm, O ;
López-Alonso, M ;
Antiñolo, G ;
Eng, C .
JOURNAL OF MEDICAL GENETICS, 1999, 36 (10) :771-774