Recessive Osteogenesis Imperfecta Caused by Missense Mutations in SPARC

被引：99

作者：

Mendoza-Londono, Roberto ^{[1
,2
,3
]}

Fahiminiya, Somayyeh ^{[4
,5
]}

Majewski, Jacek ^{[4
,5
]}

Tetreault, Martine ^{[4
,5
]}

Nadaf, Javad ^{[4
,5
]}

Kannu, Peter ^{[1
,2
,3
]}

Sochett, Etienne ^{[2
,3
,6
]}

Howard, Andrew ^{[2
,3
,7
]}

Stimec, Jennifer ^{[3
,8
]}

Dupuis, Lucie ^{[1
,2
,3
]}

Roschger, Paul ^{[9
]}

Klaushofer, Klaus ^{[9
]}

Palomo, Telma ^{[10
]}

Ouellet, Jean ^{[10
]}

Al-Jallad, Hadil ^{[10
]}

Mort, John S. ^{[10
]}

Moffatt, Pierre ^{[10
]}

Boudko, Sergei ^{[11
]}

Baechinger, Hans-Peter ^{[11
]}

Rauch, Frank ^{[10
]}

机构：

[1] Hosp Sick Children, Dept Paediat, Div Clin & Metab Genet, Toronto, ON M5G 1X8, Canada

[2] Univ Toronto, Toronto, ON M5G 1X8, Canada

[3] Hosp Sick Children, Bone Hlth Ctr, Toronto, ON M5G 1X8, Canada

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

[5] Genome Quebec Innovat Ctr, Montreal, PQ H3A 1B1, Canada

[6] Hosp Sick Children, Div Endocrinol, Dept Paediat, Toronto, ON M5G 1X8, Canada

[7] Hosp Sick Children, Dept Orthopaed Surg, Toronto, ON M5G 1X8, Canada

[8] Hosp Sick Children, Dept Diagnost Imaging, Toronto, ON M5G 1X8, Canada

[9] WGKK & AUVA Trauma Ctr Meidling, Ludwig Boltzmann Inst Osteol, Med Dept 1, Hanusch Hosp, A-1140 Vienna, Austria

[10] Shriners Hosp Children, Montreal, PQ H3G 1A6, Canada

[11] Shriners Hosp Children, Portland, OR 97239 USA

来源：

AMERICAN JOURNAL OF HUMAN GENETICS | 2015年 / 96卷 / 06期

基金：

加拿大健康研究院;

关键词：

MINERALIZATION DENSITY DISTRIBUTION; WNT1; MUTATIONS; BONE; MICE; OSTEOPOROSIS; DEFICIENT; VARIANTS; DISEASE; PROTEIN;

D O I：

10.1016/j.ajhg.2015.04.021

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Secreted protein, acidic, cysteine-rich (SPARC) is a glycoprotein that binds to collagen type I and other proteins in the extracellular matrix. Using whole-exome sequencing to identify the molecular defect in two unrelated girls with severe bone fragility and a clinical diagnosis of osteogenesis imperfecta type IV, we identified two homozygous variants in SPARC (GenBank: NM_ 003118.3; c.497G>A [p.Arg166His] in individual 1; c.787G>A [p.Glu263Lys] in individual 2). Published modeling and site-directed mutagenesis studies had previously shown that the residues substituted by these mutations form an intramolecular salt bridge in SPARC and are essential for the binding of SPARC to collagen type I. The amount of SPARC secreted by skin fibroblasts was reduced in individual 1 but appeared normal in individual 2. The migration of collagen type I alpha chains produced by these fibroblasts was mildly delayed on SDS-PAGE gel, suggesting some overmodification of collagen during triple helical formation. Pulse-chase experiments showed that collagen type I secretion was mildly delayed in skin fibroblasts from both individuals. Analysis of an iliac bone sample from individual 2 showed that trabecular bone was hypermineralized on the material level. In conclusion, these observations show that homozygous mutations in SPARC can give rise to severe bone fragility in humans.

引用

页码：979 / 985

页数：7