April 1, 2009
FSH Society, Inc. initiated fellowship publishes paper in Proceedings of the National Academy of Sciences – the first on miRNA “Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers”
Proc Natl Acad Sci U S A. 2009 Apr 14;106(15):6220-5. Epub 2009 Apr 1. Transcriptional regulation differs in affected facioscapulohumeral muscular dystrophy patients compared to asymptomatic related carriers.
Arashiro P, Eisenberg I, Kho AT, Cerqueira AM, Canovas M, Silva HC, Pavanello RC, Verjovski-Almeida S, Kunkel LM, Zatz M.
Human Genome Research Center, Department of Genetics and Evolutive Biology, Institute of Biosciences, University of São Paulo, 05508-090, São Paulo, Brazil.
Facioscapulohumeral muscular dystrophy (FSHD) is a progressive muscle disorder that has been associated with a contraction of 3.3-kb repeats on chromosome 4q35. FSHD is characterized by a wide clinical inter- and intrafamilial variability, ranging from wheelchair-bound patients to asymptomatic carriers. Our study is unique in comparing the gene expression profiles from related affected, asymptomatic carrier, and control individuals. Our results suggest that the expression of genes on chromosome 4q is altered in affected and asymptomatic individuals. Remarkably, the changes seen in asymptomatic samples are largely in products of genes encoding several chemokines, whereas the changes seen in affected samples are largely in genes governing the synthesis of GPI-linked proteins and histone acetylation. Besides this, the affected patient and related asymptomatic carrier share the 4qA161 haplotype. Thus, these polymorphisms by themselves do not explain the pathogenicity of the contracted allele. Interestingly, our results also suggest that the miRNAs might mediate the regulatory network in FSHD. Together, our results support the previous evidence that FSHD may be caused by transcriptional dysregulation of multiple genes, in cis and in trans, and suggest some factors potentially important for FSHD pathogenesis. The study of the gene expression profiles from asymptomatic carriers and related affected patients is a unique approach to try to enhance our understanding of the missing link between the contraction in D4Z4 repeats and muscle disease, while minimizing the effects of differences resulting from genetic background.
PMID: 19339494 [PubMed - in process]
[Excerpt from paper] ACKNOWLEDGMENTS. We thank all families, whose collaboration was essential
for this study, and also Constaˆ ncia Urbani. We also thank Dr. Mariz
Vainzof, Lydia Yamamoto, and Dr. Ivo Pavanello for helping with the muscle
biopsies; Richard J.L.F. Lemmers for helping with SSLP genotyping; all members
from M.Z.’s laboratory, and Genri Kawahara, Juan C. Casar, Hart Lidov,
and Anu Balasubramanian for helpful suggestions. This study was supported
by Fundac¸a˜o de Amparo a` Pesquisa do Estado de Sa˜o Paulo-Centro de Pesquisa,
Inovac¸a˜o e Difusa˜o (P.A. and M.Z.), Conselho Nacional de Desenvolvimento
Cienti´fico e Tecnolo´ gico (M.Z.), Facioscapulohumeral Society Research
Fellowship Grant FSHS-FS-005 (to P.A. and M.Z.), Instituto Nacional de Ce´ lulas-
Tronco em Doenc¸as Gene´ ticas (M.Z.), and Wellstone Center Grant
1U54HD060848–01 (to L.M.K. and M.Z.). L.M.K. is an Investigator with the
Howard Hughes Medical Institute.