Functional Assessment of TSC2 Variants Identified in Individuals with Tuberous Sclerosis Complex

被引：58

作者：

Hoogeveen-Westerveld, Marianne ^{[1
]}

Ekong, Rosemary ^{[2
]}

Povey, Sue ^{[2
]}

Mayer, Karin ^{[3
]}

Lannoy, Nathalie ^{[4
]}

Elmslie, Frances ^{[5
]}

Bebin, Martina ^{[6
]}

Dies, Kira ^{[7
]}

Thompson, Catherine ^{[8
]}

Sparagana, Steven P. ^{[8
,9
]}

Davies, Peter ^{[10
]}

van den Ouweland, Ans ^{[1
]}

Halley, Dicky ^{[1
]}

Nellist, Mark ^{[1
]}

机构：

[1] Erasmus MC, Dept Clin Genet, NL-3015 GE Rotterdam, Netherlands

[2] UCL, Res Dept Genet Evolut & Environm, London, England

[3] Ctr Human Genet & Lab Med, Martinsried, Germany

[4] Ctr Human Genet, Brussels, Belgium

[5] St George Hosp, Dept Med Genet, London, England

[6] Univ Alabama Birmingham, Dept Neurol, Birmingham, AL 35294 USA

[7] Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[8] Texas Scottish Rite Hosp Children, Dept Neurol, Dallas, TX 75219 USA

[9] Univ Texas SW Med Ctr Dallas, Dallas, TX 75390 USA

[10] Cardiff Univ, Inst Med Genet, Cardiff CF10 3AX, S Glam, Wales

来源：

HUMAN MUTATION | 2013年 / 34卷 / 01期

关键词：

tuberous sclerosis complex; TSC2; unclassified variants; functional assay; HAMARTIN COMPLEX; CELL-GROWTH; MUTATIONS; GENE; PHOSPHORYLATION; AKT;

D O I：

10.1002/humu.22202

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Tuberous sclerosis complex (TSC) is an autosomal dominant disorder caused by mutations in the TSC1 or TSC2 genes. The TSC1 and TSC2 gene products, TSC1 and TSC2, form a complex that inhibits the mammalian target of rapamycin (mTOR) complex 1 (TORC1). Here, we investigate the effects of 78 TSC2 variants identified in individuals suspected of TSC, on the function of the TSC1-TSC2 complex. According to our functional assessment, 40 variants disrupted the TSC1-TSC2-dependent inhibition of TORC1. We classified 34 of these as pathogenic, three as probably pathogenic and three as possibly pathogenic. In one case, a likely effect on splicing as well as an effect on function was noted. In 15 cases, our functional assessment did not agree with the predictions of the SIFT amino acid substitution analysis software. Our data support the notion that different, non-terminating TSC2 mutations can have distinct effects on TSC1-TSC2 function, and therefore, on TSC pathology. Hum Mutat 34:167-175, 2013. (C) 2012 Wiley Periodicals, Inc.

引用

页码：167 / 175

页数：9

共 23 条

[21] Interaction between hamartin and tuberin, the TSC1 and TSC2 gene products [J].

van Slegtenhorst, M ;

Nellist, M ;

Nagelkerken, B ;

Cheadle, J ;

Snell, R ;

van den Ouweland, A ;

Reuser, A ;

Sampson, J ;

Halley, D ;

van der Sluijs, P .

HUMAN MOLECULAR GENETICS, 1998, 7 (06) :1053-1057

[22] Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34 [J].

vanSlegtenhorst, M ;

deHoogt, R ;

Hermans, C ;

Nellist, M ;

Janssen, B ;

Verhoef, S ;

Lindhout, D ;

vandenOuweland, A ;

Halley, D ;

Young, J ;

Burley, M ;

Jeremiah, S ;

Woodward, K ;

Nahmias, J ;

Fox, M ;

Ekong, R ;

Osborne, J ;

Wolfe, J ;

Povey, S ;

Snell, RG ;

Cheadle, JP ;

Jones, AC ;

Tachataki, M ;

Ravine, D ;

Sampson, JR ;

Reeve, MP ;

Richardson, P ;

Wilmer, F ;

Munro, C ;

Hawkins, TL ;

Sepp, T ;

Ali, JBM ;

Ward, S ;

Green, AJ ;

Yates, JRW ;

Kwiatkowska, J ;

Henske, EP ;

Short, MP ;

Haines, JH ;

Jozwiak, S ;

Kwiatkowski, DJ .

SCIENCE, 1997, 277 (5327) :805-808

[23] Functional characterization of the TSC2 c.3598C>T (p.R1200W) missense mutation that co-segregates with tuberous sclerosis complex in mildly affected kindreds [J].

Wentink, M. ;

Nellist, M. ;

Hoogeveen-Westerveld, M. ;

Zonnenberg, B. ;

van der Kolk, D. ;

van Essen, T. ;

Park, S-M ;

Woods, G. ;

Cohn-Hokke, P. ;

Brussel, W. ;

Smeets, E. ;

Brooks, A. ;

Halley, D. ;

van den Ouweland, A. ;

Maat-Kievit, A. .

CLINICAL GENETICS, 2012, 81 (05) :453-461

← 1 2 3 →