Haploinsufficiency of SF3B4, a Component of the Pre-mRNA Spliceosomal Complex, Causes Nager Syndrome

被引：149

作者：

Bernier, Francois P. ^{[1
,3
]}

Caluseriu, Oana ^{[1
]}

Ng, Sarah ^{[2
]}

Schwartzentruber, Jeremy ^{[4
,5
]}

Buckinghams, Kati J. ^{[6
]}

Innes, A. Micheil ^{[1
,3
]}

Jabs, Ethylin Wang ^{[7
]}

Innis, Jeffrey W. ^{[8
,9
]}

Schuette, Jane L. ^{[8
,9
]}

Gorski, Jerome L. ^{[10
,11
]}

Byers, Peter H. ^{[12
]}

Andelfinger, Gregor ^{[13
]}

Siu, Victoria ^{[14
]}

Lauzon, Julie ^{[1
,3
]}

Fernandez, Bridget A. ^{[15
,16
]}

McMillin, Margaret ^{[6
]}

Scott, Richard H. ^{[17
,18
]}

Racher, Hilary ^{[1
]}

Majewski, Jacek ^{[19
]}

Nickerson, Deborah A. ^{[2
]}

Shendure, Jay ^{[2
]}

Bamshad, Michael J. ^{[2
,6
]}

Parboosingh, Jillian S. ^{[1
,3
]}

机构：

[1] Univ Calgary, Dept Med Genet, Calgary, AB T3B 6A8, Canada

[2] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[3] Alberta Childrens Prov Gen Hosp, Res Inst, Calgary, AB T3B 6A8, Canada

[4] McGill Univ, Montreal, PQ H3A 0G1, Canada

[5] Genome Quebec Innovat Ctr, Montreal, PQ H3A 0G1, Canada

[6] Univ Washington, Dept Pediat, Seattle, WA 98105 USA

[7] Mt Sinai Sch Med, Dept Genet & Genom Sci, New York, NY 10029 USA

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

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

[10] Univ Missouri, Columbia Sch Med, Dept Child Hlth, Columbia, MO 65212 USA

[11] Univ Missouri, Columbia Sch Med, Dept Pathol & Anat Sci, Columbia, MO 65212 USA

[12] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[13] McGill Univ, Dept Pediat, Montreal, PQ H3A 1B1, Canada

[14] Univ Western Ontario, Dept Pediat, London, ON N6A 5W9, Canada

[15] Mem Univ Newfoundland, Discipline Genet, St John, NF A1B 3V6, Canada

[16] Mem Univ Newfoundland, Discipline Med, St John, NF A1B 3V6, Canada

[17] Great Ormond St Hosp Sick Children, Dept Clin Genet, London WC1N 3JH, England

[18] Inst Child Hlth, Clin & Mol Genet Unit, London WC1N 1EH, England

[19] McGill Univ, Dept Human Genet, Montreal, PQ H3A 1B1, Canada

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2012年 / 90卷 / 05期

基金：

美国国家卫生研究院; 加拿大健康研究院;

关键词：

ACROFACIAL DYSOSTOSIS SYNDROME; DOMINANT RETINITIS-PIGMENTOSA; SPLICING FACTOR; SEQUENCING DATA; BMPR-IA; GENE; INHERITANCE; MUTATIONS;

D O I：

10.1016/j.ajhg.2012.04.004

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Nager syndrome, first described more than 60 years ago, is the archetype of a class of disorders called the acrofacial dysostoses, which are characterized by craniofacial and limb malformations. Despite intensive efforts, no gene for Nager syndrome has yet been identified. In an international collaboration, FORGE Canada and the National Institutes of Health Centers for Mendelian Genomics used exome sequencing as a discovery tool and found that mutations in SF3B4, a component of the U2 pre-mRNA spliceosomal complex, cause Nager syndrome. After Sanger sequencing of SF3B4 in a validation cohort, 20 of 35 (57%) families affected by Nager syndrome had 1 of 18 different mutations, nearly all of which were frameshifts. These results suggest that most cases of Nager syndrome are caused by haploinsufficiency of SF3B4. Our findings acid Nager syndrome to a growing list of disorders caused by mutations in genes that encode major components of the spliceosome and also highlight the synergistic potential of international collaboration when exome sequencing is applied in the search for genes responsible for rare Mendelian phenotypes.

引用

页码：925 / 933

页数：9

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