Proteomic identification of FHL1 as the protein mutated in human reducing body myopathy

Joachim Schessl, Yaqun Zou, Meagan J. McGrath, Belinda S. Cowling, Baijayanta Maiti, Steven S. Chin, Caroline Sewry, Roberta Battini, Ying Hu, Denny L. Cottle, Michael Rosenblatt, Lynn Spruce, Arupa Ganguly, Janbernd Kirschner, Alexander R. Judkins, Jeffrey A. Golden, Hans Hilmar Goebel, Francesco Muntoni, Kevin M. Flanigan, Christina A. MitchellCarsten G. Bönnemann

Research output: Contribution to journalArticlepeer-review

133 Scopus citations


Reducing body myopathy (RBM) is a rare disorder causing progressive muscular weakness characterized by aggresome-like inclusions in the myofibrils. Identification of genes responsible for RBM by traditional genetic approaches has been impossible due to the frequently sporadic occurrence in affected patients and small family sizes. As an alternative approach to gene identification, we used laser microdissection of intracytoplasmic inclusions identified in patient muscle biopsies, followed by nanoflow liquid chromatography-tandem mass spectrometry and proteomic analysis. The most prominent component of the inclusions was the Xq26.3-encoded four and a half LIM domain 1 (FHL1) protein, expressed predominantly in skeletal but also in cardiac muscle. Mutational analysis identified 4 FHL1 mutations in 2 sporadic unrelated females and in 2 families with severely affected boys and less-affected mothers. Transfection of kidney COS-7 and skeletal muscle C2C12 cells with mutant FHL1 induced the formation of aggresome-like inclusions that incorporated both mutant and wild-type FHL1 and trapped other proteins in a dominant-negative manner. Thus, a novel laser microdissection/proteomics approach has helped identify both inherited and de novo mutations in FHL1, thereby defining a new X-linked protein aggregation disorder of muscle.

Original languageEnglish
Pages (from-to)904-912
Number of pages9
JournalJournal of Clinical Investigation
Issue number3
StatePublished - Mar 2008


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