Journal article

Association Study of Exon Variants in the NF-kappa B and TGF beta Pathways Identifies CD40 as a Modifier of Duchenne Muscular Dystrophy

Luca Bello, Kevin M Flanigan, Robert B Weiss, Pietro Spitali, Annemieke Aartsma-Rus, Francesco Muntoni, Irina Zaharieva, Alessandra Ferlini, Eugenio Mercuri, Sylvie Tuffery-Giraud, Mireille Claustres, Volker Straub, Hanns Lochmuller, Andrea Barp, Sara Vianello, Elena Pegoraro, Jaya Punetha, Heather Gordish-Dressman, Mamta Giri, Craig M McDonald Show all

The American Journal of Human Genetics | CELL PRESS | Published : 2016


The expressivity of Mendelian diseases can be influenced by factors independent from the pathogenic mutation: in Duchenne muscular dystrophy (DMD), for instance, age at loss of ambulation (LoA) varies between individuals whose DMD mutations all abolish dystrophin expression. This suggests the existence of trans-acting variants in modifier genes. Common single nucleotide polymorphisms (SNPs) in candidate genes (SPP1, encoding osteopontin, and LTBP4, encoding latent transforming growth factor β [TGFβ]-binding protein 4) have been established as DMD modifiers. We performed a genome-wide association study of age at LoA in a sub-cohort of European or European American ancestry (n = 109) from the ..

View full abstract


Awarded by Association Francaise contre les Myopathies

Awarded by European Union

Awarded by Telethon Italy Foundation

Awarded by U.S. Department of Defense

Awarded by U.S. Department of Education/NIDRR

Awarded by U.S. National Institutes of Health/NIAMS

Awarded by Medical Research Council



Funding Acknowledgements

We would like to thank all participants and their families. We gratefully acknowledge Stanley F. Nelson and Richard T. Wang (UCLA) for generating Exome Chip data, Akanchha Kesari (Children's National Medical Center) for help with genotyping, Bruno F. Gavassini (University of Padova) for technical help with immunoblot experiments, Michela Guglieri and Kate Bushby (Newcastle University) for providing clinical data, and biobank staff Dan Cox and Mojgan Reza (Newcastle University) for processing samples. L.B. was supported by an Italian Ministry of Education PhD grant for the Doctorate School of Medical, Clinical, and Experimental Science at the University of Padova. We acknowledge funding from Association Francaise contre les Myopathies (support to Bio-NMD, grants 15092 and 17724); Dutch Duchenne Parent Project (support to P.S.); the European Union (support to Bio-NMD grant 241665, Neuromics grant 305121, RD-Connect grant 305444); the Italian Duchenne Parent Project (support to A.F.); the Medical Research council Centre for Neuromuscular Diseases Biobanks (support to London and Newcastle Biobanks), part of Eurobiobank; National Institute for Health Research Biomedical Research Centre at Great Ormond Street Hospital for Children, NHS Foundation Trust, and University College London; Telethon Italy Foundation (support to Nemo Centers and Padova Neuromuscular Biobank, grant GTB12001D); the U.S. Department of Defense (support to CINRG, grant #W81XWH-12-1-0417); the U.S. Department of Education/NIDRR (support to CINRG, grants H133B031118 and H133B090001); and the U.S. National Institutes of Health/NIAMS (support to CINRG, grant R01AR061875).