New insights into the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and impairment of the WRC-mediated actin dynamics

被引：33

作者：

Begemann, Anais ^{[1
]}

Sticht, Heinrich ^{[2
]}

Begtrup, Amber ^{[3
]}

Vitobello, Antonio ^{[4
,5
]}

Faivre, Laurence ^{[4
,6
]}

Banka, Siddharth ^{[7
,8
]}

Alhaddad, Bader ^{[9
]}

Asadollahi, Reza ^{[1
]}

Becker, Jessica ^{[10
,11
]}

Bierhals, Tatjana ^{[12
]}

Brown, Kathleen E. ^{[13
]}

Bruel, Ange-Line ^{[4
,5
]}

Brunet, Theresa ^{[9
]}

Carneiro, Maryline ^{[14
]}

Cremer, Kirsten ^{[10
,11
]}

Day, Robert ^{[15
]}

Denomme-Pichon, Anne-Sophie ^{[4
,5
]}

Dyment, Dave A. ^{[16
,17
]}

Engels, Hartmut ^{[10
,11
]}

Fisher, Rachel ^{[18
]}

Goh, Elaine S. ^{[19
,20
]}

Hajianpour, M. J. ^{[21
]}

Machado Haertel, Lucia Ribeiro ^{[22
]}

Hauer, Nadine ^{[23
]}

Hempel, Maja ^{[12
]}

Herget, Theresia ^{[12
]}

Johannsen, Jessika ^{[24
]}

Kraus, Cornelia ^{[23
]}

Le Guyader, Gwenael ^{[25
]}

Lesca, Gaetan ^{[26
,27
]}

Mau-Them, Frederic Tran ^{[4
,5
]}

McDermott, John Henry ^{[7
,8
]}

McWalter, Kirsty ^{[3
]}

Meyer, Pierre ^{[28
]}

Ounap, Katrin ^{[29
,30
]}

Popp, Bernt ^{[23
,31
]}

Reimand, Tiia ^{[29
,30
,32
]}

Riedhammer, Korbinian M. ^{[9
,33
]}

Russo, Martina ^{[1
]}

Sadleir, Lynette G. ^{[34
]}

Saenz, Margarita ^{[13
]}

Schiff, Manuel ^{[35
,36
]}

Schuler, Elisabeth ^{[37
]}

Syrbe, Steffen ^{[37
]}

Van der Ven, Amelie Theresa ^{[12
]}

Verloes, Alain ^{[38
,39
]}

Willems, Marjolaine ^{[40
]}

Zweier, Christiane ^{[23
]}

Steindl, Katharina ^{[1
]}

Zweier, Markus ^{[1
]}

机构：

[1] Univ Zurich, Inst Med Genet, Schlieren, Switzerland

[2] Friedrich Alexander Univ Erlangen Nurnberg, Inst Biochem, Emil Fischer Ctr, Erlangen, Germany

[3] GeneDx, Gaithersburg, MD USA

[4] Univ Bourgogne, INSERM UMR Equipe GAD 1231, Dijon, France

[5] CHU Dijon Bourgogne, Unite Fonct Innovat Diagnost Genom Malad Rarer, FHU TRANSLAD, Dijon, France

[6] CHU Dijon Bourgogne, Ctr Genet, FHU TRANSLAD, Ctr Reference Malad Rares Anomalies Dev & Syndrom, Dijon, France

[7] Manchester Univ NHS Fdn Trust, Manchester Ctr Genom Med, St Marys Hosp, Hlth Innovat Manchester, Manchester, Lancs, England

[8] Univ Manchester, Div Evolut & Genom Sci, Sch Biol Sci, Fac Biol Med & Hlth, Manchester, Lancs, England

[9] Tech Univ Munich, Sch Med, Klinikum Rechts Isar, Inst Human Genet, Munich, Germany

[10] Univ Bonn, Inst Human Genet, Sch Med, Bonn, Germany

[11] Univ Hosp Bonn, Bonn, Germany

[12] Univ Klinikum Hamburg Eppendorf, Inst Human Genet, Hamburg, Germany

[13] Univ Colorado, Childrens Hosp Colorado, Anschutz Med Campus, Aurora, CO USA

[14] Lyon Univ Hosp, Dept Neuropediat, Lyon, France

[15] Univ Otago, Dept Biochem, Canc Res Lab, Dunedin, New Zealand

[16] Univ Ottawa, Dept Pediat, Ottawa, ON, Canada

[17] Univ Ottawa, Childrens Hosp, Eastern Ontario Res Inst, Ottawa, ON, Canada

[18] Univ Michigan, Div Pediat Genet Metab & Genom Med, Dept Pediat, Ann Arbor, MI 48109 USA

[19] Trillium Hlth Partners, Lab Med & Genet, Mississauga, ON, Canada

[20] Trillium Hlth Partners, Inst Better Hlth, Mississauga, ON, Canada

[21] East Tennessee State Univ, Quillen Coll Med, Med Genet, Dept Pediat, Johnson City, TN USA

[22] Hosp Santa Catarina Blumenau, Blumenau, Brazil

[23] Friedrich Alexander Univ Erlangen Nurnberg FAU, Inst Human Genet, Erlangen, Germany

[24] Univ Med Ctr Hamburg Eppendorf, Dept Pediat, Hamburg, Germany

[25] CHU Poitiers, Poitiers, France

[26] Lyon Univ Hosp, Dept Med Genet, Lyon, France

[27] Claude Bernard Lyon 1 Univ, CNRS UMR 5292, INSERM U1028, Lyon, France

[28] Univ Montpellier, CNRS, INSERM, PhyMedExp,Dept Pediat Neurol,CHU Montpellier, Montpellier, France

[29] Univ Tartu, Inst Clin Med, Dept Clin Genet, Tartu, Estonia

[30] Tartu Univ Hosp, Dept Clin Genet, United Labs, Tartu, Estonia

[31] Univ Leipzig Hosp & Clin, Inst Human Genet, Leipzig, Germany

[32] Univ Tartu, Inst Biomed & Translat Med, Dept Biomed, Tartu, Estonia

[33] Tech Univ Munich, Sch Med, Dept Nephrol, Klinikum Rechts Isar, Munich, Germany

[34] Univ Otago, Dept Paediat & Child Hlth, Wellington, New Zealand

[35] Univ Paris, Necker Univ Hosp, AP HP, Reference Ctr Inborn Errors Metab,Fac Med Paris D, Paris, France

[36] Inst Imagine, Inserm UMRS 1163, Paris, France

[37] Univ Hosp Heidelberg, Dept Pediat, Heidelberg, Germany

[38] Univ Paris Diderot, UMR1141, INSERM, Sorbonne Paris Cite, Paris, France

[39] Robert Debre Univ Hosp, AP HP, Genet Dept, Paris, France

[40] CHRU Montpellier, Dept Genet Med, Montpellier, France

[41] Univ Zurich, Zurich Ctr Integrat Human Physiol, Zurich, Switzerland

[42] Univ Zurich, Neurosci Ctr Zurich, Zurich, Switzerland

[43] Swiss Fed Inst Technol, Zurich, Switzerland

来源：

GENETICS IN MEDICINE | 2021年 / 23卷 / 03期

基金：

瑞士国家科学基金会; 英国惠康基金;

关键词：

intellectual disability; epilepsy; CYFIP2; WAVE-regulatory complex (WRC); WASF; WAVE-REGULATORY COMPLEX; MUTATIONS; PHOSPHORYLATION; BEHAVIORS; DORSAL; CYFIP2;

D O I：

10.1038/s41436-020-01011-x

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Purpose A few de novo missense variants in the cytoplasmic FMRP-interacting protein 2 (CYFIP2) gene have recently been described as a novel cause of severe intellectual disability, seizures, and hypotonia in 18 individuals, with p.Arg87 substitutions in the majority. Methods We assembled data from 19 newly identified and all 18 previously published individuals with CYFIP2 variants. By structural modeling and investigation of WAVE-regulatory complex (WRC)-mediated actin polymerization in six patient fibroblast lines we assessed the impact of CYFIP2 variants on the WRC. Results Sixteen of 19 individuals harbor two previously described and 11 novel (likely) disease-associated missense variants. We report p.Asp724 as second mutational hotspot (4/19 cases). Genotype-phenotype correlation confirms a consistently severe phenotype in p.Arg87 patients but a more variable phenotype in p.Asp724 and other substitutions. Three individuals with milder phenotypes carry putative loss-of-function variants, which remain of unclear pathogenicity. Structural modeling predicted missense variants to disturb interactions within the WRC or impair CYFIP2 stability. Consistent with its role in WRC-mediated actin polymerization we substantiate aberrant regulation of the actin cytoskeleton in patient fibroblasts. Conclusion Our study expands the clinical and molecular spectrum of CYFIP2-related neurodevelopmental disorder and provides evidence for aberrant WRC-mediated actin dynamics as contributing cellular pathomechanism.

引用

页码：543 / 554

页数：12

共 4 条

[1] Expanding the clinical and molecular spectrum of the novel CYFIP2-related neurodevelopmental disorder and functional proof of aberrant WRC-mediated actin dynamics
Begemann, A.
Sticht, H.
McWalter, K.
Vitobello, A.
Faivre, L.
Alhaddad, B.
Banka, S.
Becker, J.
Bierhals, T.
Brown, K.
Bruel, A.
Brunet, T.
Carneiro, M.
Cremer, K.
Day, R.
Denomme-Pichon, A.
Dyment, D. A.
Engels, H.
Fisher, R.
Glassford, M.
Goh, E. S.
Hajianpour, M.
Haertel, L. R. M.
Hauer, N.
Hempel, M.
Herget, T.
Kraus, C.
Le Guyader, G.
Lesca, G.
Mau-Them, F. T.
McDermott, J. H.
Meyer, P.
Ounap, K.
Popp, B.
Reimand, T.
Riedhammer, K. M.
Russo, M.
Sadleir, L.
Schuler, E.
Siegel, G.
Syrbe, S.
Van der Ven, A. T.
Verloes, A.
Willems, M.
Zweier, C.
Steindl, K.
Zweier, M.
Rauch, A.
EUROPEAN JOURNAL OF HUMAN GENETICS, 2020, 28 (SUPPL 1) : 329 - 331
[2] New insights into the clinical and molecular spectrum of the MADD-related neurodevelopmental disorder
Abdel-Salam, Ghada M. H.
Abdel-Hamid, Mohamed S.
JOURNAL OF HUMAN GENETICS, 2024, 69 (06) : 263 - 270
[3] GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder
Shieh, Christine
Jones, Natasha
Vanle, Brigitte
Au, Margaret
Huang, Alden Y.
Silva, Ana P. G.
Lee, Hane
Douine, Emilie D.
Otero, Maria G.
Choi, Andrew
Grand, Katheryn
Taff, Ingrid P.
Delgado, Mauricio R.
Hajianpour, M. J.
Seeley, Andrea
Rohena, Luis
Vernon, Hilary
Gripp, Karen W.
Vergano, Samantha A.
Mahida, Sonal
Naidu, Sakkubai
Sousa, Ana Berta
Wain, Karen E.
Challman, Thomas D.
Beek, Geoffrey
Basel, Donald
Ranells, Judith
Smith, Rosemarie
Yusupov, Roman
Freckmann, Mary-Louise
Ohden, Lisa
Davis-Keppen, Laura
Chitayat, David
Dowling, James J.
Finkel, Richard
Dauber, Andrew
Spillmann, Rebecca
Pena, Loren D. M.
Metcalfe, Kay
Splitt, Miranda
Lachlan, Katherine
McKee, Shane A.
Hurst, Jane
Fitzpatrick, David R.
Morton, Jenny E. V.
Cox, Helen
Venkateswaran, Sunita
Young, Juan I.
Marsh, Eric D.
Nelson, Stanley F.
GENETICS IN MEDICINE, 2020, : 878 - 888
[4] GATAD2B-associated neurodevelopmental disorder (GAND): clinical and molecular insights into a NuRD-related disorder (vol 19, pg 238, 2020)
Shieh, Christine
Jones, Natasha
Vanle, Brigitte
Au, Margaret
Huang, Alden Y.
Silva, Ana P. G.
Lee, Hane
Douine, Emilie D.
Otero, Maria G.
Choi, Andrew
Grand, Katheryn
Taff, Ingrid P.
Delgado, Mauricio R.
Hajianpour, M. J.
Seeley, Andrea
Rohena, Luis
Vernon, Hilary
Gripp, Karen W.
Vergano, Samantha A.
Mahida, Sonal
Naidu, Sakkubai
Sousa, Ana Berta
Wain, Karen E.
Challman, Thomas D.
Beek, Geoffrey
Basel, Donald
Ranells, Judith
Smith, Rosemarie
Yusupov, Roman
Freckmann, Mary-Louise
Ohden, Lisa
Davis-Keppen, Laura
Chitayat, David
Dowling, James J.
Finkel, Richard
Dauber, Andrew
Spillmann, Rebecca
Pena, Loren D. M.
Metcalfe, Kay
Splitt, Miranda
Lachlan, Katherine
Mckee, Shane A.
Hurst, Jane
Fitzpatrick, David R.
Morton, Jenny E. V.
Cox, Helen
Venkateswaran, Sunita
Young, Juan I.
Marsh, Eric D.
Nelson, Stanley F.
GENETICS IN MEDICINE, 2020, 22 (04) : 822 - 822

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