Stickler syndrome caused by COL2A1 mutations: genotype-phenotype correlation in a series of 100 patients

被引：107

作者：

Hoornaert, Kristien P. ^{[1
]}

Vereecke, Inge ^{[1
]}

Dewinter, Chantal ^{[1
]}

Rosenberg, Thomas ^{[2
]}

Beemer, Frits A. ^{[3
]}

Leroy, Jules G. ^{[1
]}

Bendix, Laila ^{[4
]}

Bjorck, Erik ^{[5
]}

Bonduelle, Maryse ^{[6
]}

Boute, Odile ^{[7
]}

Cormier-Daire, Valerie ^{[8
]}

De Die-Smulders, Christine ^{[9
]}

Dieux-Coeslier, Anne ^{[7
]}

Dollfus, Helene ^{[10
]}

Elting, Mariet ^{[11
]}

Green, Andrew ^{[12
,13
]}

Guerci, Veronica I. ^{[14
]}

Hennekam, Raoul C. M. ^{[15
,16
]}

Hilhorts-Hofstee, Yvonne ^{[17
]}

Holder, Muriel ^{[7
]}

Hoyng, Carel ^{[18
]}

Jones, Kristi J. ^{[19
,20
]}

Josifova, Dragana ^{[21
]}

Kaitila, Ilkka ^{[22
]}

Kjaergaard, Suzanne ^{[23
]}

Kroes, Yolande H. ^{[3
]}

Lagerstedt, Kristina ^{[5
]}

Lees, Melissa ^{[15
]}

LeMerrer, Martine ^{[8
]}

Magnani, Cinzia ^{[24
]}

Marcelis, Carlo ^{[25
]}

Martorell, Loreto ^{[26
]}

Mathieu, Michele ^{[27
]}

McEntagart, Meriel ^{[28
]}

Mendicino, Angela ^{[29
]}

Morton, Jenny ^{[30
]}

Orazio, Gabrielli ^{[31
]}

Paquis, Veronique ^{[32
]}

Reish, Orit ^{[33
]}

Simola, Kalle O. J. ^{[34
]}

Smithson, Sarah F. ^{[35
]}

Temple, Karen I. ^{[36
]}

Van Aken, Elisabeth ^{[37
]}

Van Bever, Yolande ^{[38
]}

van den Ende, Jenneke ^{[39
]}

Van Hagen, Johanna M. ^{[40
]}

Zelante, Leopoldo ^{[41
]}

Zordania, Riina ^{[42
]}

De Paepe, Anne ^{[1
]}

Leroy, Bart P. ^{[1
,37
]}

机构：

[1] Univ Antwerp Hosp, Dept Med Genet, Prins Boudewijnlaan, Belgium

[2] Gordon Norrie Ctr Genet Eye Dis, Natl Eye Clin, Hellerup, Denmark

[3] Ctr Med Genet, Utrecht, Netherlands

[4] Univ So Denmark, Vejle Hosp, Dept Clin Genet, Vejle, Denmark

[5] Karolinska Univ Hosp, Dept Clin Genet, Stockholm, Sweden

[6] UZ Brussel, Ctr Med Genet, Brussels, Belgium

[7] Hop Jeanne de Flandre, Clin Genet Ctr, Lille, France

[8] Univ Paris 05, Necker Enfants Malad Hosp, Dept Med Genet, Paris, France

[9] Univ Hosp Maastricht, Dept Clin Genet, Maastricht, Netherlands

[10] Hop Univ Strasbourg, Ctr Reference Affect Rares & Genet Ophthalmol CAR, Strasbourg, France

[11] Vrije Univ Amsterdam, Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[12] Natl Ctr Med Genet Our Ladys Hosp, Dublin, Ireland

[13] Univ Coll Dublin, Sch Med & Med Sci, Dublin 2, Ireland

[14] IRCCS Burlo Garofolo, Metab Dis Unit, Trieste, Italy

[15] UCL, Inst Child Hlth, Clin & Mol Genet Unit, London, England

[16] Univ Amsterdam, Acad Med Ctr, Dept Pediat, NL-1105 AZ Amsterdam, Netherlands

[17] Leiden Univ, Med Ctr, Dept Clin Genet, Leiden, Netherlands

[18] Radboud Univ Nijmegen, Med Ctr, Dept Ophthalmol, NL-6525 ED Nijmegen, Netherlands

[19] Childrens Hosp Westmead, Western Sydney Genet Program, Sydney, NSW, Australia

[20] Univ Sydney, Discipline Paediat & Child Hlth, Sydney, NSW 2006, Australia

[21] Guys Hosp, Dept Clin Genet, London SE1 9RT, England

[22] Univ Helsinki, Cent Hosp, Dept Clin Genet, Helsinki, Finland

[23] Rigshosp, Dept Clin Genet, DK-2100 Copenhagen, Denmark

[24] Univ Hosp Parma, Dept Paediat, Parma, Italy

[25] Radboud Univ Nijmegen Med Ctr, Dept Human Genet, Nijmegen, Netherlands

[26] Hosp St Joan de Deu, Dept Genet, Barcelona, Spain

[27] CHU Nord, Amiens, France

[28] St Georges Univ London, London, England

[29] ASL RME, DTMI, UOS Genet, Rome, Italy

[30] Birmingham Womens Hosp, Clin Genet Unit, Birmingham, W Midlands, England

[31] Osped G Salesi, Dept Clin Genet, Ancona, Italy

[32] Hop Arghet, Dept Clin Genet, Nice, France

[33] Assaf Harofeh Med Ctr, Inst Genet, IL-70300 Zerifin, Israel

[34] Tampere Univ Hosp, Dept Pediat, Tampere, Finland

[35] St Michaels Hosp, Dept Clin Genet, Bristol, Avon, England

[36] Univ Southampton, Div Human Genet, Acad Unit Genet Med, Southampton, Hants, England

[37] Ghent Univ Hosp, Dept Ophthalmol, B-9000 Ghent, Belgium

[38] Erasmus MC, Dept Clin Genet, Rotterdam, Netherlands

[39] Univ Antwerp Hosp, Ctr Med Genet, Antwerp, Belgium

[40] Univ Med Ctr, Dept Clin Genet, Amsterdam, Netherlands

[41] IRCCS Casa Sollievo Sofferenza, Gen Med Serv, San Giovanni Rotondo, Italy

[42] Tallinn Childrens Hosp, Tallinn, Estonia

[43] Ghent Univ Hosp, Ctr Heart, B-9000 Ghent, Belgium

来源：

EUROPEAN JOURNAL OF HUMAN GENETICS | 2010年 / 18卷 / 08期

关键词：

COL2A1; Stickler syndrome; genotype-phenotype correlation; type II collagenopathies; splice site mutation; GEL-ELECTROPHORESIS; SITE MUTATION; COL11A1; GENE; COLLAGEN; DOMINANT; EXON-2; SUBSTITUTION; PREDICTION; DYSPLASIA; SPECTRUM;

D O I：

10.1038/ejhg.2010.23

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Stickler syndrome is an autosomal dominant connective tissue disorder caused by mutations in different collagen genes. The aim of our study was to define more precisely the phenotype and genotype of Stickler syndrome type 1 by investigating a large series of patients with a heterozygous mutation in COL2A1. In 188 probands with the clinical diagnosis of Stickler syndrome, the COL2A1 gene was analyzed by either a mutation scanning technique or bidirectional fluorescent DNA sequencing. The effect of splice site alterations was investigated by analyzing mRNA. Multiplex ligation-dependent amplification analysis was used for the detection of intragenic deletions. We identified 77 different COL2A1 mutations in 100 affected individuals. Analysis of the splice site mutations showed unusual RNA isoforms, most of which contained a premature stop codon. Vitreous anomalies and retinal detachments were found more frequently in patients with a COL2A1 mutation compared with the mutation-negative group (P<0.01). Overall, 20 of 23 sporadic patients with a COL2A1 mutation had either a cleft palate or retinal detachment with vitreous anomalies. The presence of vitreous anomalies, retinal tears or detachments, cleft palate and a positive family history were shown to be good indicators for a COL2A1 defect. In conclusion, we confirm that Stickler syndrome type 1 is predominantly caused by loss-of-function mutations in the COL2A1 gene as >90% of the mutations were predicted to result in nonsense-mediated decay. On the basis of binary regression analysis, we developed a scoring system that may be useful when evaluating patients with Stickler syndrome. European Journal of Human Genetics (2010) 18, 872-880; doi:10.1038/ejhg.2010.23; published online 24 February 2010

引用

页码：872 / 880

页数：9

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