Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy

被引：5

作者：

Toepf, Ana ^{[1
,2
]}

Cox, Dan ^{[1
]}

Zaharieva, Irina T. ^{[2
,3
]}

Di Leo, Valeria ^{[1
,2
,4
]}

Sarparanta, Jaakko ^{[5
,6
]}

Jonson, Per Harald ^{[5
,6
]}

Sealy, Ian M. ^{[7
,8
]}

Smolnikov, Andrei ^{[9
]}

White, Richard J. ^{[7
,8
]}

Vihola, Anna ^{[5
,6
,10
,11
]}

Savarese, Marco ^{[5
,6
]}

Merteroglu, Munise ^{[7
,12
]}

Wali, Neha ^{[13
]}

Laricchia, Kristen M. ^{[14
,15
]}

Venturini, Cristina ^{[16
]}

Vroling, Bas ^{[17
]}

Stenton, Sarah L. ^{[14
,18
]}

Cummings, Beryl B. ^{[12
]}

Harris, Elizabeth ^{[1
,2
,19
]}

Marini-Bettolo, Chiara ^{[1
,2
]}

Diaz-Manera, Jordi ^{[1
]}

Henderson, Matt ^{[20
]}

Barresi, Rita ^{[21
]}

Duff, Jennifer ^{[1
]}

England, Eleina M. ^{[14
]}

Patrick, Jane ^{[13
]}

Al-Husayni, Sundos ^{[22
]}

Biancalana, Valerie ^{[23
]}

Beggs, Alan H. ^{[22
]}

Bodi, Istvan ^{[24
]}

Bommireddipalli, Shobhana ^{[25
,26
]}

Boennemann, Carsten G. ^{[27
]}

Cairns, Anita ^{[28
]}

Chiew, Mei-Ting ^{[29
]}

Claeys, Kristl G. ^{[30
,31
]}

Cooper, Sandra T. ^{[25
]}

Davis, Mark R. ^{[29
]}

Donkervoort, Sandra ^{[26
,27
]}

Erasmus, Corrie E. ^{[32
]}

Fassad, Mahmoud R. ^{[33
,34
]}

Genetti, Casie A. ^{[22
]}

Grosmann, Carla ^{[35
]}

Jungbluth, Heinz ^{[36
,37
]}

Kamsteeg, Erik-Jan ^{[38
]}

Lornage, Xaviere ^{[23
]}

Loescher, Wolfgang N. ^{[39
]}

Malfatti, Edoardo ^{[40
]}

Manzur, Adnan ^{[3
]}

Marti, Pilar ^{[41
,42
]}

Mongini, Tiziana E. ^{[43
]}

机构：

[1] Newcastle Univ, Translat & Clin Res Inst, John Walton Muscular Dystrophy Res Ctr, Newcastle Upon Tyne, England

[2] Newcastle Hosp NHS Fdn Trust, Newcastle Upon Tyne, England

[3] UCL Great Ormond St Inst Child Hlth & Great Ormond, Dubowitz Neuromuscular Ctr, London, England

[4] Univ Trieste, Dept Life Sci, Trieste, Italy

[5] Folkhalsan Res Ctr, Helsinki, Finland

[6] Univ Helsinki, Dept Med & Clin Genet, Medicum, Helsinki, Finland

[7] Queen Mary Univ London, Sch Biol & Behav Sci, London, England

[8] Univ Cambridge, Jeffrey Cheah Biomed Ctr, Dept Med, Cambridge Inst Therapeut Immunol & Infect Dis CITI, Cambridge, England

[9] Univ New South Wales, Sch Biotechnol & Biomol Sci, Sydney, NSW, Australia

[10] Tampere Univ, Neuromuscular Res Ctr, Tampere, Finland

[11] Univ Hosp, Tampere, Finland

[12] Univ Padua, Dept Biol, Lab Angiogenesis & Canc Metab, Padua, Italy

[13] Wellcome Genome Campus, Wellcome Sanger Inst, Hinxton, England

[14] Broad Inst MIT & Harvard, Program Med & Populat Genet, Cambridge, MA USA

[15] Massachusetts Gen Hosp, Analyt & Translat Genet Unit, Boston, MA USA

[16] Univ Coll London Hosp, Div Infect, London, England

[17] Bioprodict, Nijmegen, Netherlands

[18] Boston Childrens Hosp, Dept Pediat, Div Genet & Genom, Boston, MA USA

[19] Inst Genet Med, Northern Genet Serv, Newcastle Upon Tyne, England

[20] Newcastle Tyne Hosp NHS Fdn Trust, Musculoskeletal Unit, Newcastle Upon Tyne, England

[21] IRCCS San Camillo Hosp, Venice, Italy

[22] Harvard Med Sch, Div Genet & Genom, Manton Ctr Orphan Dis Res, Boston Childrens Hosp, Boston, MA USA

[23] Univ Strasbourg, Inst Genet & Biol Mol & Cellulaire IGBMC, INSERM, CNRS,UMR7104,U1258, Illkirch Graffenstaden, France

[24] Kings Coll Hosp NHS Fdn Trust, Dept Clin Neuropathol, London, England

[25] Univ Sydney, Childrens Hosp Westmead, Kids Neurosci Ctr, Westmead, NSW, Australia

[26] Childrens Med Res Inst, Westmead, NSW, Australia

[27] Natl Inst Neurol Disorders & Stroke, Neuromuscular & Neurogenet Disorders Childhood Sec, NIH, Bethesda, MD USA

[28] Queensland Childrens Hosp, Neurosci Dept, Brisbane, Qld, Australia

[29] PathWest Lab Med, Dept Diagnost Genom, Perth, WA, Australia

[30] Univ Hosp Leuven, Dept Neurol, Leuven, Belgium

[31] Katholieke Univ Leuven, Dept Neurosci, Lab Muscle Dis & Neuropathies, Leuven, Belgium

[32] Radboud Univ Nijmegen Med Ctr, Amalia Childrens Hosp, Donders Inst Brain Cognit & Behav, Dept Pediat Neurol, Nijmegen, Netherlands

[33] Newcastle Univ, Wellcome Ctr Mitochondrial Res, Translat & Clin Res Inst, Fac Med Sci, Newcastle Upon Tyne, England

[34] Newcastle Tyne Hosp NHS Fdn Trust, NHS Highly Specialised Serv Rare Mitochondrial Dis, Newcastle Upon Tyne, England

[35] Univ Calif San Diego, Rady Childrens Hosp, Dept Neurol, San Diego, CA USA

[36] Guys & St Thomas Hosp NHS Fdn Trust, Evelinas Children Hosp, Dept Paediat Neurol Neuromuscular Serv, London, England

[37] Kings Coll London, Fac Life Sci & Med FoLSM, Randall Ctr Cell & Mol Biophys, Muscle Signalling Sect, London, England

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

[39] Med Univ Innsbruck, Dept Neurol, Innsbruck, Austria

[40] Univ Paris Est, Henri Mondor Hosp, Neuromuscular Reference Ctr Nord Est Ile De France, APHP,U955,INSERM, Creteil, France

[41] Ctr Invest Biomed Red Enfermedades Raras CIBERER, Madrid, Spain

[42] IIS La Fe, Neuromuscular Res Unit, Valencia, Spain

[43] Univ Torino, Dept Neurosci Rita Levi Montalcini, Turin, Italy

[44] Univ Valencia, Dept Med, Valencia, Spain

[45] Hosp Univ & Politecn La Fe, Neurol Dept, Neuromuscular Dis Unit, Valencia, Spain

[46] Natl Inst Neurosci, Natl Ctr Neurol & Psychiat, Dept Neuromuscular Res, Tokyo, Japan

[47] RIKEN BioResource Res Ctr, Tsukuba, Japan

[48] Auckland Dist Hlth Board, Starship Childrens Hlth, Auckland, New Zealand

[49] Univ Louvain, Ctr Reference Neuromusculaire, Clin Univ St Luc, Brussels, Belgium

[50] Rutgers New Jersey Med Sch, Dept Pediat, Div Clin Genet, Newark, NJ USA

来源：

NATURE GENETICS | 2024年 / 56卷 / 03期

基金：

澳大利亚国家健康与医学研究理事会; 芬兰科学院; 英国生物技术与生命科学研究理事会; 英国惠康基金; 英国医学研究理事会;

关键词：

GIRDLE MUSCULAR-DYSTROPHY; LINKAGE ANALYSIS; SPLICING FACTORS; GENE; MUTATION; CARDIOMYOPATHY; LOCALIZATION; VARIANT; FAMILY; RBM20;

D O I：

10.1038/s41588-023-01651-0

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

In digenic inheritance, pathogenic variants in two genes must be inherited together to cause disease. Only very few examples of digenic inheritance have been described in the neuromuscular disease field. Here we show that predicted deleterious variants in SRPK3, encoding the X-linked serine/argenine protein kinase 3, lead to a progressive early onset skeletal muscle myopathy only when in combination with heterozygous variants in the TTN gene. The co-occurrence of predicted deleterious SRPK3/TTN variants was not seen among 76,702 healthy male individuals, and statistical modeling strongly supported digenic inheritance as the best-fitting model. Furthermore, double-mutant zebrafish (srpk3-/-; ttn.1+/-) replicated the myopathic phenotype and showed myofibrillar disorganization. Transcriptome data suggest that the interaction of srpk3 and ttn.1 in zebrafish occurs at a post-transcriptional level. We propose that digenic inheritance of deleterious changes impacting both the protein kinase SRPK3 and the giant muscle protein titin causes a skeletal myopathy and might serve as a model for other genetic diseases. Digenic inheritance of deleterious variants in serine/arginine protein kinase 3 (SRPK3) and titin (TTN) leads to a progressive early onset skeletal muscle myopathy. Zebrafish double mutants exhibit a similar myopathy phenotype accompanied by myofibrillar disorganization.

引用

页码：395 / 407

页数：31

共 50 条

[1] Digenic inheritance involving a muscle-specific protein kinase and the giant titin protein causes a skeletal muscle myopathy
Ana Töpf
Dan Cox
Irina T. Zaharieva
Valeria Di Leo
Jaakko Sarparanta
Per Harald Jonson
Ian M. Sealy
Andrei Smolnikov
Richard J. White
Anna Vihola
Marco Savarese
Munise Merteroglu
Neha Wali
Kristen M. Laricchia
Cristina Venturini
Bas Vroling
Sarah L. Stenton
Beryl B. Cummings
Elizabeth Harris
Chiara Marini-Bettolo
Jordi Diaz-Manera
Matt Henderson
Rita Barresi
Jennifer Duff
Eleina M. England
Jane Patrick
Sundos Al-Husayni
Valerie Biancalana
Alan H. Beggs
Istvan Bodi
Shobhana Bommireddipalli
Carsten G. Bönnemann
Anita Cairns
Mei-Ting Chiew
Kristl G. Claeys
Sandra T. Cooper
Mark R. Davis
Sandra Donkervoort
Corrie E. Erasmus
Mahmoud R. Fassad
Casie A. Genetti
Carla Grosmann
Heinz Jungbluth
Erik-Jan Kamsteeg
Xavière Lornage
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[J]. Nature Genetics, 2024, 56 : 395 - 407
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